Fredericamycin derivatives

ABSTRACT

The invention relates to novel fredericamycin derivatives, to drugs containing said derivatives or the salts thereof, and to the use of the fredericamycin derivatives for treating diseases, especially cancer diseases.

REFERENCE TO RELATED APPLICATIONS

This application a continuation of application Ser. No. 10/509,066 filedSep. 24, 2004, which is a national stage application (under 35 U.S.C.§371) of PCT/EP03/02922, filed Mar. 20, 2003, which claims benefit ofGerman application 102 13 580.0, filed Mar. 26, 2002 and Germanapplication 102 48 451.1 filed Oct. 17, 2002. The entire contents ofeach of these applications are hereby incorporated by reference hereinin their entirety.

FIELD OF THE INVENTION

The invention relates to novel fredericamycin derivatives, to drugscontaining said derivatives or the salts thereof, and to the use of thefredericamycin derivatives for treating diseases, particularly cancerdiseases.

BACKGROUND OF THE INVENTION

Fredericamycin has been isolated 1981 from Streptomyces griseus, anddemonstrates anti-cancer activity.

Fredericamycin and several fredericamycin derivatives are known.

In Heterocycles 37 (1994) 1893-1912, J. Am. Chem. Soc. 116 (1994)9921-9926, J. Am. Chem. Soc. 116 (1994) 11275-11286, J. Am. Chem. Soc.117 (1995) 11839-11849, JP 2000-072752, and in J. Am. Chem. Soc. 123(2001), various total syntheses of fredericamycin A have been described,some being enantio-selective.

In U.S. Pat. No. 4,673,768, alkali salts of the fredericamycin A aredescribed. In U.S. Pat. No. 4,584,377, fredericamycin derivatives aredescribed, particularly derivatives acylated in ring E and F. In U.S.Pat. No. 5,166,208, fredericamycin derivatives are described as well,particularly derivatives carrying thio and amino substituents in ring F.The derivatives are generated semi-synthetically or fully synthetically.

SUMMARY OF THE INVENTION

Surprisingly it was found that fredericamycin derivatives, especiallythose derivatized in ring A, represent potent drugs. Also, a possibilitywas found to introduce such residues in ring A semi-synthetically, withwhich the water solubility and/or the biological effect, the spectrum ofaction in comparison with fredericamycin, can be significantlyincreased. Furthermore, an alternative method was found to makefredericamycin and its derivatives water-soluble by generatingcyclodextrin inclusion compounds.

The invention relates to novel fredericamycin derivatives with thegeneral Formula Ia or Ib:

wherein in each,R1 means H, C₁-C₆ alkyl, cycloalkyl, C₁-C₄ alkylcycloalkyl,R2 means H, C₁-C₁₄ alkyl, C₂-C₁₄ alkenyl, aryl, C₁-C₄ alkylaryl,heteroaryl, C₁-C₄ alkyl heteroaryl, C₂-C₄ alkenylheteroaryl, cycloalkyl,C₁-C₄ alkylcycloalkyl, heterocycloalkyl, C₁-C₄ alkylheterocycloalkyl,C_(m)H_(2m+o−p)Y_(p) (with m=1 to 6, for o=1, p=1 to 2m+o; for m=2 to 6,o=−1, p=1 to 2m+o; for m=4 to 6, o=−2, p=1 to 2m+o; Y=independentlyselected from the group consisting of halogen, OH, OR21, NH₂, NHR21,NR21R22, SH, SR21), (CH₂)_(r)CH₂NHCOR21, (CH₂)_(r)CH₂OCOR21,(CH₂)_(r)CH₂NHCSR21, (CH₂)_(r)CH₂S(O)nR21, with n=0, 1, 2,(CH₂)_(r)CH₂SCOR21, (CH₂)_(r)CH₂OSO₂—R21, (CH₂)_(r)CHO, (CH₂)_(r)CH═NOH,(CH₂)_(r)CH(OH)R21, —(CH₂)_(r)CH═NOR21, (CH₂)_(r)CH═NOCOR21,(CH₂)_(r)CH═NOCH₂CONR21R22, (CH₂)_(r)CH═NOCH(CH₃)CONR21R22,—(CH₂)_(r)CH═NOC(CH₃)₂CONR21R22, (CH₂)_(r)CH═N—NHCO—R23,(CH₂)_(r)CH═N—NHC(O)NH—R23, (CH₂)_(r)CH═N—NHC(S)NH—R23,(CH₂)_(r)CH═N—NHC(NH)NH—R23, (CH₂)_(r)CH═N—NHC(NH)—R23,(CH₂)_(r)CH═N—NHCO—CH₂NHCOR21, (CH₂)_(r)CH═N—O—CH₂NHCOR21,(CH₂)_(r)CH═N—NHCS—R23, (CH₂)_(r)CH═CR24R25 (trans or cis),(CH₂)_(r)COOH, (CH₂)_(r)COOR21, (CH₂)_(r)CONR21R22, —(CH₂)_(r)CH═NR21,(CH₂)_(r)CH═N—NR21R22,

and the (CH₂)_(r)-chain elongated residue(CH₂)_(r)CH═N—N—(C₃NX′R211R212R213R214) (with X′═NR215, O, S, and R211,R212, R213, R214, R215 being independently H or C₁-C₆ alkyl),—(CH₂)_(r)CH═N—NHSO₂ aryl, —(CH₂)_(r)CH═N—NHSO₂ heteroaryl, with r=0, 1,2, 3, 4, 5, preferably 0,R21, R22 are independently H, C₁-C₁₄ alkyl, C₁-C₁₄ alkanoyl, C₁-C₆alkylhydroxy, C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ alkylamino-C₁-C₆alkyl, C₁-C₆ alkylamino-di-C₁-C₆ alkyl, cycloalkyl, C₁-C₄alkylcycloalkyl, heterocycloalkyl, C₁-C₄ alkylheterocycloalkyl, aryl,aryloyl, C₁-C₄ alkylaryl, heteroaryl, heteroaryloyl, C₁-C₄alkylheteroaryl, cycloalkanoyl, C₁-C₄ alkanoylcycloalkyl,heterocycloalkanoyl, C₁-C₄ alkanoylheterocycloalkyl, C₁-C₄ alkanoylaryl,C₁-C₄ alkanoylheteroaryl, mono- and di-sugar residues linked through a Catom which would carry an OH residue in the sugar, wherein the sugarsare independently selected from the group consisting of glucuronic acidand its stereo isomers at all optical atoms, aldopentoses, aldohexoses,including their desoxy compounds (as e.g. glucose, desoxyglucose,ribose, desoxyribose), or R21 and R22, together with the N, form a ringwith 4, 5, 6, 7, or 8 members, which may optionally contain stillanother heteroatom selected from the group N, O, S,R23 independently of R21, has the same meanings as R21, orCH₂-pyridinium salts, CH₂-tri-C₁-C₆ alkylammonium salts, CONH₂, CSNH₂,CN, CH₂CN,R24 independently of R21, has the same meanings as R21, or H, CN, COCH₃,COOH, CO OR21, CONR21R22, NH₂, NHCOR21,R25 independently of R21, has the same meanings as R21, or H, CN, COCH₃,COOH, COOR21, CONR21R22, NH₂, NHCOR21,R24, R25 together with the N, form a ring with 4, 5, 6, 7, or 8 members,which may optionally contain still another heteroatom selected from thegroup N, O, S,R3 means H, F, Cl, Br, I, OH, OR31, NO₂, NH₂, NHR31, NR31R32, NHCHO,NHCOR31, NHCOCF₃, CH_(3−m)hal_(m), (with hal=Cl, F, particularly F, andm=1, 2, 3), OCOR31,R31, R32 are independently C₁-C₆ alkyl, or R31 and R32, together withthe N, form a ring with 4, 5, 6, 7, or 8 members, which may optionallycontain still another heteroatom selected from the group N, O, S,R5 means H, C₁-C₂₀ alkyl, cycloalkyl, C₂-C₂₀ alkenyl, C₂-C₁₀ alkinyl,C₁-C₄ alkyl cycloalkyl, heterocycloalkyl, C₁-C₄ alkyl heterocycloalkyl,aryl, C₁-C₄ alkylaryl, heteroaryl, C₁-C₄ alkylheteroaryl,C_(m)H_(2m+o−p)Y_(p) (with m=1 to 6, for o=1, p=1 to 2m+o; for m=2 to 6,o=−1, p=1 to 2m+o; for m=4 to 6, o=−2, p=1 to 2m+o; Y=independentlyselected from the group consisting of halogen, OH, OR51, NH₂, NHR51,NR51R52, SH, SR21), (CH₂)_(s)CH₂NHCOR51, (CH₂)_(s)CH₂NHCSR51,(CH₂)_(s)CH₂S(O)nR51, with n=0, 1, 2, (CH₂)_(s)CH₂SCOR51,(CH₂)_(s)CH₂OCOR51, (CH₂)_(s)CH₂OSO₂—R51, (CH₂)_(s)CH(OH)R51,(CH₂)_(s)COOH, (CH₂)_(s)COOR51, (CH₂)_(s)CONR51R52, with s=0, 1, 2, 3,4, 5, preferably 0, mono- and di-sugar residues linked through a C atomwhich would carry an OH residue in the sugar, wherein the sugars areindependently selected from the group consisting of glucuronic acid andits stereo isomers at all optical atoms, aldopentoses, aldohexoses,including their desoxy compounds (as e.g. glucose, desoxyglucose,ribose, desoxyribose), with the mono-sugar residues such asaldopentoses, aldohexoses, including their desoxy compounds (as e.g.glucose, desoxyglucose, ribose, desoxyribose) being preferred, with R51,R52 which are capable of independently adopting the meaning of R21, R22,R4, R6, R7 independently mean H, C₁-C₆ alkyl, CO—R41,R41 independently from R21, has the same meanings as R21,X means O, S, NH, N—R8, wherein R8 independently from R5 may adopt thesame meaning as R5, or R5 and R8, together with the N, form a ring with4, 5, 6, 7, or 8 members, which may optionally contain still anotherheteroatom selected from the group N, O, S,or X—R5 may together be H,Y means O, S, NR9, wherein R9 may be H or C₁-C₆ alkyl,as well their stereoisomers, tautomers, and their physiologicallytolerable salts or inclusion compounds, wherein the residues for FormulaIa may not concomitantly adopt the following meaning, except in case ofcyclodextrin inclusion compounds: R1: H, C₁-C₆ alkyl, R2: C₁-C₆ alkyl,C₂-C₆ alkenyl, R3: H, R4 and R6 identical, and independently H, C₁-C₆alkyl, CO—R41, with R41 being C₁-C₆ alkyl, aryl, and R7 being H, C₁-C₆alkyl, Y: O, and for Formula Ib: R1: H, R2: pentyl, 1-pentenyl,3-pentenyl, 1,3-pentdienyl, R3: H, R4 and R6 being H, and X—R5 beingmethoxy, Y: O. Preferably, the substituents do not concomitantly adoptthe following meaning: R1, R3: H, R2: H, alkyl, hydroxyalkyl,particularly monohydroxyalkyl, alkoxyalkyl, CF₃, (CH₂)_(r)COOH, CHO,CONH₂, (CH₂)_(r)CH₂NHCO alkyl, (CH₂)_(r)CH₂OCO alkyl, (CH₂)_(r)CH₂NHCSalkyl, CH═NOH, CH═NO alkyl, aryl, alkylaryl, alkylheteroaryl, alkenyl,hydroxyalkenyl, particularly monohydroxyalkenyl, R4, R6, R7: H, alkyl,X—R5: H, R5: H, alkyl, aryl.

Preferred are compounds of Formula IIa or IIb

wherein the meaning of the residues R1-R41, X is as described above,their tautomers and their physiologically tolerable salts or inclusioncompounds, wherein the residues for Formula Ia may not concomitantlyadopt the following meaning, except in the case of cyclodextrininclusion compounds: R1: H, C₁-C₆ alkyl, R2: C₁-C₆ alkyl, C₂-C₆ alkenyl,R3: H, R4 and R6 identical, and independently H, C₁-C₆ alkyl, CO—R41,with R41 being C₁-C₆ alkyl, aryl, and R7 being H, C₁-C₆ alkyl, Y: O, andfor Formula Ib: R1: H, R2: pentyl, 1-pentenyl, 3-pentenyl,1,3-pentdienyl, R3: H, R4 and R6 being H, and X—R5 being methoxy, Y: O.

DETAILED DESCRIPTION OF THE INVENTION

The invention further relates to compounds of Formula Ia, Ib, IIa orIIb, in which the residues R, except for R2, have the above describedmeanings, and the water solubility of R2 is at least two times higher,preferably at least five timer higher, more preferred at least ten timeshigher, especially preferred at least fifty time higher, particularlyone hundred times higher, or even five hundred times higher than of R2being CH═CH—CH═CH—CH₃, when all other residues are maintained. Theincrease in the water solubility is achieved e.g. by introduction ofgroups which can form additional hydrogen bonds, and/or are polar,and/or are ionic. A key intermediate are compounds with an aldehydefunction in R2.

For R2 preferred is also the group of the residues C_(m)H_(2m+o−p)Y_(p)(with m=1 to 6, for o=1, p=1 to 2m+o; for m=2 to 6, o=−1, p=1 to 2m+o;for m=4 to 6, o=−2, p=1 to 2m+o; Y=independently selected from the groupof halogen, OH, OR21, NH₂, NHR21, NR21R22, SH, SR21),(CH₂)_(r)CH₂NHCOR21, (CH₂)_(r)CH₂OCOR21, (CH₂)_(r)CH₂NHCSR21,(CH₂)_(r)CH₂S(O)nR21, with n=0, 1, 2, (CH₂)_(r)CH₂SCOR21,(CH₂)_(r)CH₂OSO₂—R21, (CH₂)_(r)CH(OH)R21, (CH₂)_(r)COOH,(CH₂)_(r)COOR21, (CH₂)_(r)CONR21R22. Still particularly preferred is thegroup of the aldehyde-derived residues (CH₂)_(r)CHO, (CH₂)_(r)CH═NOH,—(CH₂)_(r)CH═NOR21, (CH₂)_(r)CH═NOCOR21, (CH₂)_(r)CH═NOCH₂CONR21R22,(CH₂)_(r)CH═N—NHCO—R23, (CH₂)_(r)CH═N—NHC(O)NH—R23,(CH₂)_(r)CH═N—NHC(S)NH—R23, (CH₂)_(r)CH═N—NHC(NH)NH—R23,(CH₂)_(r)CH═N—NHC(NH)—R23, (CH₂)_(r)CH═N—NHCO—CH₂NHCOR21,(CH₂)_(r)CH═N—O—CH₂NHCOR21, (CH₂)_(r)CH═N—NHCS—R23, (CH₂)_(r)CH═CR24R25(trans or cis), (CH₂)_(r)CH═NR21, (CH₂)_(r)CH═N—NR21R22,

and the (CH₂)_(r)-chain elongated residue(CH₂)_(r)CH═N—N—(C₃NX′R211R212R213R214) (with X′═NR215, O, S, and R211,R212, R213, R214, R215 being independently H or C₁-C₆ alkyl),—(CH₂)_(r)CH═N—NHSO₂ aryl, (CH₂)_(r)CH═N—NHSO₂ heteroaryl,(CH₂)_(r)CH═CH heteroaryl, with r=0, 1, 2, 3, 4, 5, preferably 0.

From the aldehydes and thereof derived compounds, such are preferred inwhich at least R1 or r3 are not H, if R4 to R7 are H or alkyl.

Preferred residues in R2 are further heteroaryl, cycloaryl, C₁-C₄alkylcycloalkyl, heterocycloalkyl, C₁-C₄ alkyl heterocycloalkyl,C_(m)H_(2m+o−p)Y_(p) (with m=1 to 6, for o=1, p=1 to 2m+o; for m=2 to 6,o=−1, p=1 to 2m+o; for m=4 to 6, o=−2, p=1 to 2m+o; Y=independentlyselected from the group of halogen, OH, OR21, NH₂, NHR21, NR21R22, SH,SR21), CH₂NHCOR21, CH₂NHCSR21, CH₂S(O)nR21, with n=0, 1, 2, CH₂SCOR21,CH₂OSO₂—R21, CH(OH)R21, CH═NOCOR21, —CH═NOCH₂CONR21R22,—CH═NOCH(CH₃)—CONR21R22, CH═NOC(CH₃)₂CONR11R22, CH═N—NHCO—R23,—CH═N—NHCO—CH₂NHCOR21, CH═N—O—CH₂NHCOR21, —CH═N—NHCS—R23, CH═CR24R25(trans or cis), CONR21R22, —CH═NR21, —CH═N—NR21R22,

(with X′═NR215, O, S, and R211, R212, R213, R214, R215 beingindependently H or C₁-C₆ alkyl), CH═N—NHSO₂ aryl, H═N—NHSO₂ heteroaryl.

Furthermore, compounds as described above are preferred, in which R3means F, Cl, Br, I, OH, OR31, NO₂, NH₂, NHR31, NR31R32, NHCHO, NHCOR31,NHCOCF₃, CH_(3−m)hal_(m), (with hal=Cl, F, particularly F, and m=1, 2,3), OCOR31, with the above described meanings for R31, R32.

Also preferred are compounds as described above, in which X means N orS, especially when R3 is H or halogen, and/or R2 is alkenyl,particularly butadienyl or 1,3-pentdienyl.

Also preferred are compounds as described above, in which X—R5 is OH,and particularly their salts, and preferred in compounds of Formula Iaor IIa, since this acidic OH group may easily be deprotonized, whichincreases the water solubility and/or the biological efficacy.Furthermore preferred are still compounds as described above, whereinthe residues R preferably independently adopt one or more of thefollowing meanings:

R1 means H, C₁-C₅ alkyl, cycloalkyl, especially H,R2 means C₁-C₅ alkyl, C₁-C₄ alkylaryl, C₂-C₅ alkenyl, heteroaryl, C₁-C₄alkylheteroaryl, C₂-C₄ alkenylheteraryl, CHF₂, CF₃, polyol side chain,particularly CHOH—CHOH—CHOH—CHOH—CH₃, CHOH—CHOH—CH═CH—CH₃,CH═CH—CHOH—CHOH—CH₃, CH₂Y (Y═F, Cl, Br, I), CH₂NH₂, CH₂NR21R22,CH₂NHCOR23, CH₂NHCSR23, CH₂SH, CH₂S(O)nR21, with n=0, 1, 2, CH₂SCOR21,particularly CH₂OH, CH₂OR21, CH₂OSO₂—R21, particularly CHO, CH(OR21)₂,CH(SR21)₂, CN, CH═NOH, CH═NOR21, CH═NOCOR21, CH═N—NHCO—R32, CH═CR24, R25(trans or cis), particularly COOH (particularly their physiologicallytolerable salts), COOR21, CONR21R22, —CH═NR21, —CH═N—NR21R22,

(with X′═NR215, O, S, and R211, R212, R213, R214, R215 beingindependently H or C₁-C₆ alkyl), —CH═N—NHSO₂ aryl, —CH═N—NHSO₂heteroaryl, CH═N—NHCO—R23,R21, R22 independently mean C₁-C₆ alkyl, cycloalkyl, aryl, C₁-C₄alkylaryl, heteroaryl, C₁-C₄ alkylheteroaryl,R23 independently of R21, has the same meanings as R21, orCH₂-pyridinium salts, CH₂-tri-C₁-C₆ alkylammonium salts,R24 independently of R21, has the same meanings as R21, or H, CN, COCH₃,COOH, COOR21, CONR21R22, NH₂, NHCOR21,R25 independently of R21, has the same meanings as R21, or H, CN, COCH₃,COOH, COOR21, CONR21R22, NH₂, NHCOR21,R24, R25 together mean C₄-C₈ cycloalkyl,R3 means F, Cl, Br, I, NO₂, NH₂, NHCOR31,R31 independently means C₁-C₆ alkyl,R5 means H, C₁-C₆ alkyl, particularly C₁-C₃ alkyl, C₃-C₈ cycloalkyl,C₃-C₈ cycloalkenyl, C₁-C₆ alkenyl, C₁-C₆ alkinyls, C₁-C₄alkylcycloalkyl, heterocycloalkyl, C₁-C₄ alkylheterocycloalkyl, aryl,C₁-C₄ alkylaryl, heteroaryl, C₁-C₄ alkylheteroaryl, C_(m)H_(2m+o−p)Y_(p)(with m=1 to 6, for o=1, p=1 to 2m+o; for m=2 to 6, o=−1, p=1 to 2m+o;for m=4 to 6, o=−2, p=1 to 2m+o; Y=independently selected from the groupconsisting of halogen, OH, OR21, NH₂, NHR21, NR21R22, SH, SR21),particularly preferred is hydroxyalkyl with one or more OH groups,R4, R6, R7 independently means H, C₁-C₅ alkyl, CO—R41,R41 independently from R21, has the same meanings as R21,X means O, S, NH, N—R8,Y means O, S, NH,as well their stereoisomers, tautomers, and their physiologicallytolerable salts or inclusion compounds, wherein the residues for FormulaIa may not concomitantly adopt the following meaning, except in case ofcyclodextrin inclusion compounds: R1: H, C₁-C₆ alkyl, R2: C₁-C₆ alkyl,C₂-C₆ alkenyl, R3: H, R4 and R6 are identical, and independently are H,C₁-C₆ alkyl, CO—R41, with R41 being C₁-C₆ alkyl, aryl, and R7 being H,C₁-C₆ alkyl, and for Formula Ib: R1: H, R2: pentyl, 1-pentenyl,3-pentenyl, 1,3-pentdienyl, R3: H, R4 and R6 being H, and X—R5 beingmethoxy.

O, S, particularly 0, are preferred for Y.

O, NH, N—R8 are preferred for X.

H, methyl, ethyl, propyl, particularly methyl, are preferred for R5.

H, methyl, ethyl, propyl, particularly methyl, are preferred for R8.

OCH₃, NH₂, N(CH₃)₂ are preferred for XR5.

For R2 also preferred is the residue —CHOHCHOHCHOHCHOHCH₃.

Furthermore, the following residues are preferred for R2:—CHCH-2-methyl-4-thiazyl, particularly

wherein R particularly is alkyl or NHCO alkyl, CH═NOR21, with R21 beingmethyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl, benzyl, halogenbenzyl, particularly fluorobenzyl and chlorobenzyl, —CH₂CH₂ morpholinyl.

Especially preferred are the compounds, the stereo isomers, tautomers,and physiologically tolerable salts or inclusion compounds of which,selected from the group consisting of the compounds of the examples andthe compounds, demonstrate combinations of the various substituents ofthe examples.

Particularly preferred for R3 is H, F, Cl, Br, J, particularly F, Cl,Br, J.

Particularly preferred for R2 is C₁-C₈ alkyl, C₂-C₈ alkenyl, CH═NOR1,with R21 being C₁-C₈ alkyl, C₁-C₈ alkenyl, aryl or heteroaryl, C₁-C₂alkylaryl, particularly benzyl, C₁-C₂ alkylheteroaryl, wherein aryl orheteroaryl in particular have only one ring system which may besubstituted once or twice with a substituent such as halogen, methyl,CF₃, OH, OMe.

Particularly preferred are derivatives of fredericamycin A in which onlythe above indicated, particularly preferred meanings of R2 and/or R3 arerealized.

The invention furthermore relates to drugs containing the abovecompounds of Formula I or II together with the usual carriers andadjuvants.

Also preferred are the above mentioned drugs in combination with otheragents for cancer treatment.

These compounds according to the invention are used for preparation ofdrugs for treatment of cancers, particularly such that may be treated byinhibition of the topoisomerases I and/or II. Cancers that can betreated with the substances according to the invention are e.g.leukemia, lung cancer, melanomas, uterus tumors, prostate tumors andcolon tumors.

Also, fredericamycin A and its derivatives act against an unknown targetin the cell cycle leading to apoptosis in tumor cells.

Furthermore, the compounds according to the invention, and compoundswhich have concomitantly adopted the following meanings in Formula Ia:R1: H, C₁-C₆ alkyl, R2: C₁-C₆ alkyl, C₂-C₆ alkenyl, R3: H, R4 and R6identically and independently H, C₁-C₆ alkyl, CO—R41, with R41 beingC₁-C₆ alkyl, aryl, and R7 being H, C₁-C₆ alkyl, and in Formula Ib: R1:H, R2: pentyl, 1-pentenyl, 3-pentenyl, 1,3-pentdienyl, R3: H, R4 and R6being H and X—R5 being methoxy, are used for preparation of drugs fortreatment of neurodermitis, parasites and for immunosuppression.

The invention also relates to a method for preparation of fredericamycinderivatives in which R2 as intermediate is —CHOHCHOHCHOHCHOHCH₃. Thesecompounds are preferably transformed into aldehydes for furtherderivatization.

In the description and the claims, the substituents are described by thefollowing definitions:

The term “alkyl” by itself or as part of another substituent means alinear or branched alkyl chain radical of the respectively indicatedlength, in which optionally a CH₂ group may be substituted by a carbonylfunction. Thus, C₁₋₄ alkyl may be methyl, ethyl, 1-propyl, 2-propyl,2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl, C₁₋₆ alkyl, e.g.C₁₋₄ alkyl, pentyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl,3-hexyl, 4-methyl-1-pentyl, or 3,3-dimethylbutyl.

The term “C₁-C₆ alkylhydroxy” by itself or as part of anothersubstituent means a linear or branched alkyl chain radical of therespectively indicated length which may be saturated or unsaturated, andwhich carries an OH group, e.g. hydroxymethyl, hydroxymethyl,1-hydroxypropyl, 2-hydroxypropyl.

The term “alkenyl” by itself or as part of another substituent means alinear or branched alkyl chain radical with one or more C═C double bondsof the respectively indicated length, several double bonds beingpreferably conjugated. Thus, C₂₋₆ alkenyl may for example be ethenyl,1-propenyl, 2-propenyl, 2-methyl-2-propenyl, 2-methyl-1-propenyl,1-butenyl, 2-butenyl, 1,3-butdienyl, 2,4-butdienyl, 1-pentenyl,2-pentenyl, 3-pentenyl, 1,3-pentdienyl, 2,4-pentdienyl, 1,4-pentdienyl,1-hexenyl, 2-hexenyl, 1,3-hediexyl, 4-methyl-1-pentenyl, or3,3-dimethylbutenyl.

The term “alkinyl” by itself or as part of another substituent means alinear or branched alkyl chain radical with one or more C—C triple bondsof the respectively indicated length. Thus, C₂₋₆ alkinyl may for examplebe ethinyl, 1-propinyl, 2-propinyl, 2-methyl-2-propinyl,2-methyl-1-propinyl, 1-butinyl, 2-butinyl, 1,3-butdiinyl, 2,4-butdiinyl,1-pentinyl, 2-pentinyl, 3-pentinyl, 1-hexinyl, 2-hexinyl,4-methyl-1-pentinyl, or 3,3-dimethylbutinyl.

The term “halogen” stands for fluorine, chlorine, bromine, iodine,preferably bromine and chlorine.

The term “NR21R22” preferably stands for a dialkylamino group, whereinthe two alkyl groups together with the N can form a ring with 5 or 6members with optionally one more heteroatom N or O.

The term “cycloalkyl” by itself or as part of another Substituentcomprises unsaturated (mono or poly, preferably mono) or saturated,cyclic carbohydrate groups with 3 to 10 C atoms, preferably 3 to 8 Catoms, such as e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclohex-2-enyl, cyclohex-3-enyl, cyclohex-2,4-dienyl,4-methylcyclohexyl, 3-methylcyclohexyl, cycloheptyl or cyclooctyl.Saturated cycloalkyls are preferred. The cycloalkyls may be substitutedwith up to 3 substituents, preferably with up to 1 substituent, whereinthe substituents independently can have the meaning C₁-C₆ alkyl, OH,NO₂, CN, CF₃, OR11, SH, SR11, C₁-C₆ alkylhydroxy, C₁-C₆ alkyl-OR11,COOH, COOR11, NH₂, NHR11, NR11R12, halogen, aryl, C₁-C₄ alkylaryl,heteroaryl, C₁-C₄ heteroalkylaryl, wherein the residues R11 and R12independently can mean C₁-C₁₀ alkyl, cycloalkyl, C₁-C₄ alkylcycloalkyl.

The term “heterocycloalkyl” by itself or as part of another substituentincludes cycloalkyl groups, wherein up to two CH₂ groups may besubstituted by oxygen, sulfur or nitrogen atoms, and one or two otherCH₂ groups may be substituted by one or two carbonyl function(s),carbothionyl function(s), or a carbonyl function and a carbothionylfunction, for example pyrrolidine, piperidine, morpholine or

The heterocycloalkyls may be substituted as with the cycloalkyls.

The term “aryl” by itself or as part of another substituent includesaromatic ring systems with up to 3 rings, in which at least 1 ringsystem is aromatic, and those with up to 3 substituents, preferably upto 1 substituent, wherein the substituents independently can have themeaning C₁-C₆ alkyl, OH, NO₂, CN, CF₃, OR11, SH, SR11, C₁-C₆alkylhydroxy, C₁-C₆ alkyl-OR11, COOH, COOR11, NH₂, NHR11, NR11R12,halogen, wherein the residues R11 and R12 independently can mean C₁-C₁₀alkyl, cycloalkyl, C₁-C₄ alkylcycloalkyl, or R11 and R12, together withthe N, form a ring with 4, 5, 6, 7 or 8 members optionally containingstill another heteroatom selected from the group N, O, S.

Apart from phenyl and 1-naphthyl and 2-naphthyl, preferred aryls are:

The term “heteroaryl” by itself or as part of another substituentincludes aromatic ring systems with up to 3 rings and with up to 3identical or different heteroatoms N, S, O, in which at least 1 ringsystem is aromatic, and those with up to 3 substituents, preferably upto 1 substituent, wherein the substituents independently can have themeaning C₁-C₆ alkyl, OH, NO₂, CN, CF₃, OR11, SH, SR11, C₁-C₆alkylhydroxy, C₁-C₆ alkyl-OR11, COOH, COOR11, NH₂, NHCOR11, NHR11,NR11R12, halogen, or phenyl, wherein the residues R11 and R12independently can have the above indicated meanings.

Preferred heteroaryls are:

The term “ring system” generally refers to rings with 3, 4, 5, 6, 7, 8,9, or 10 members. Preferred are rings with 5 and 6 members. Furthermore,ring systems with one or 2 annelated rings are preferred.

The compounds of Formula I may be present as such, or, if they containacidic or basic groups, in the form of their salts with physiologicallytolerable bases or acids. Examples for such acids are: hydrochloricacid, citric acid, trifluoracetic acid, tartaric acid, lactic acid,phosphoric acid, methane sulfonic acid, acetic acid, formic acid, maleicacid, fumaric acid, succinic acid, hydroxysuccinic acid, sulfuric acid,glutaric acid, aspartic acid, pyruvic acid, benzoic acid, glucuronicacid, oxalic acid, ascorbic acid, and acetylglycine. Examples for basesare alkali ions, preferably Na, K, particularly preferred thetri-potassium and tri-sodium salts, alkaline earth ions, preferably C,Mg, ammonium ions.

The compounds according to the invention may be administered orally inthe usual way. The application may also be i.v., i.m., with vapors, orsprays through the nasopharynx.

The dosage depends on age, condition and weight of the patient as wellas on the type of application. Usually, the daily dose of the activeingredient per person is between 0.1 μg/kg and 1 g/kg orally. Thisdosage may be given as 2 to 4 split dosages, or once per day as a slowrelease form.

The novel compounds may be used in the usual solid or liquidpharmaceutical application forms, e.g. as tablets, film tablets,capsules, powder, granules, coated tablets, solutions, or sprays. Theseare produced in the usual way. The agents can be processed with theusual pharmaceutical adjuvants such as tablet binders, fillers,preservatives, disintegrants, flow regulators, plasticizers, wettingagents, dispersants, emulsifiers, solvents, retardation agents,antioxidants, and/or propellants (see H. Sucker et al.: PharmazeutischeTechnologie, Thieme-Verlag, Stuttgart, 1978). Usually, the so obtainedapplication forms contain the active ingredient in amounts of 0.1 to 99percent per weight.

Experimental Part

Fredericamycin A can be prepared by fermentation or fully syntheticallyaccording to the known methods. The reduced forms of the Formulas Ib andIIb can be obtained from the appropriate compounds of Formulas Ia andIIa using mild reducing agents.

Preparation of the Substances

For synthesis of water soluble fredericamycin derivatives,fredericamycin (1) was first hydroxylized with osmium(IV)oxide at thediene side chain. The resulting compound (2) shows significantly higherwater solubility compared to the original compound fredericamycin (1).In order to further increase the water solubility, (2) was transformedinto the tri-potassium salt (3) (see diagram 1).

The fredericamycin tetrol (2) serves, among others, as an importantintermediate for the synthesis of other fredericamycin derivatives withincreased solubility and/or better action profile. By iodate cleavagewith sodium periodate or carrier-bound periodate, the tetrol side chainmay be degraded with very high yields to fredericamycin aldehyde (4)(see diagram 2).

The fredericamycin aldehyde (4) can be reacted with acylhydrazones,hydroxylamine, and O-alkylhydroxylamine to the appropriate hydrazone(see diagram 3), or oxime and oximether (see diagram 4). The reactioncan be performed at room temperature in solvents such as DMF orpyridine, and is finished after a few minutes to hours.

Synthesis of Hydrazones

TABLE 1 Example/compound R m/e λ_(max)(nm) 5/118

601.3 504.0 6/119

635.2 486.0

R Compound Example

111 18

105 19

113 20

Synthesis of Oximether

TABLE 2 Example/compound R m/e λ_(max)(nm) 7/122 —H 516.1 500.0 8/120—CH₃ 531.2 500.0 9/121

607.2 504.0 10/123 

678.1 504.1 21/116 

630.1 504.0

Analogously, the compounds 100-242 can be generated according to theinstructions below (table 3). The hereby used hydrazines, hydrazones andhydroxylamines are available commercially, or have been producedaccording to instructions known from the literature.

TABLE 3 Formula for table 3:

Calculated Actual Example/Compound R1 R2 mass mass UV_(nm) Yield 100

592.1230 593.10 500 95 101

661.1056 662.11 500 95 102

620.1179 621.11 492 95 103

620.1179 621.11 500 95 104

567.1026 568.11 500 80 105 (19)

583.1339 584.10 492 95 106

609.1019 610.09 492 95 107

634.1335 635.13 492 95 108

574.0794 558.05 492 95 109

625.0791 626.08 492 95 110

672.1492 673.15 492 95 111

598.1699 599.14 492 95 112

586.0971 587.10 492 95 113 (20)

631.055 632.05 500 95 114

582.1022 583.13 492 95 115

634.1335 635.16 492 70 116

629.1645 630.14 492 85 117

557.1182 558.11 500 95 118

600.1492 601.16 492 85 119

635.1414 635.13 495 85 120 (8)

530.0961 531.12 492 90 121 (9)

606.1274 607.16 492 95 122

516.0804 517.11 482 95 123 (10)

678.1332 679.14 500 95 124

634.1335 635.15 492 95 125

558.1022 559.12 492 95 126

640.1805 614.13 492 95 127

640.0884 641.10 492 95 128

640.0900 641.10 492 95 129

623.1288 624.13 500 90 130

614.1284 615.13 492 95 131

655.1914 656.19 492 50 132

642.1597 643.17 492 60 133

586.1335 587.15 492 70 134

628.1805 629.17 492 70 135

587.1539 588.14 492 90 136

752.1885 753.19 492 85 137

601.1696 602.19 492 70 138

626.0840 627.07 500 95 139

695.0666 696.06 500 95 140

654.0789 655.07 500 95 141

654.0789 655.07 500 95 142

601.0636 602.06 500 90 143

617.0949 618.08 500 95 144

643.0629 644.05 500 95 145

668.0946 669.07 500 95 146

608.0404 609.07 500 95 147

659.0401 660.07 500 95 148

706.1102 707.16 500 95 149

632.1309 633.16 500 95 150

620.0582 621.09 500 95 151

664.9965 645.31 500 95 152

616.0633 617.10 500 95 153

668.0946 669.13 500 95 154

663.1255 664.16 500 95 155

591.,0792 592.11 500 95 156

634.1102 635.14 500 95 157

669.1024 669.12 500 95 158

564.0571 565.09 500 95 159

640.0884 641.12 500 95 160

550.0415 551.06 500 95 161

712.0943 713.10 500 95 162

668.0946 669.09 500 95 163

592.0633 593.07 500 90 164

674.1415 675.11 500 95 165

675.0494 675.03 500 90 166

674.0510 675.02 500 95 167

657.0898 658.06 500 95 168

648.0895 649.07 500 95 169

689.1524 690.15 500 60 170

676.1208 677.13 500 60 171

620.0946 621.11 500 70 172

662.1415 663.12 500 70 173

621.1150 622.10 500 60 174

786.1495 787.16 500 90 175

635.1306 636.10 500 75 176

670.0334 670.99 500 95 177

739.0161 739.99 500 95 178

698.0284 699.00 500 90 179

698.0284 699.00 500 90 180

645.0130 645.99 492 70 181

661.0443 662.01 492 95 182

687.0124 688.99 492 95 183

712.0440 713.03 500 95 184

651.9899 653.04 500 95 185

702.9895 704.02 492 95 186

750.0597 751.10 500 95 187

676.0804 677.10 492 95 188

664.0076 665.05 500 95 189

708.9460 709.99 492 95 190

660.0127 661.05 492 95 191

712.0440 713.08 492 70 192

707.0750 708.06 500 95 193

635.0287 636.02 500 95 194

678.0597 679.06 500 95 195

713.0518 713.03 500 95 196

608.0066 609.03 492 95 197

684.0379 685.05 492 95 198

593.9909 595.01 492 95 199

756.0437 757.00 500 90 200

712.0440 713.00 500 90 201

636.0127 637.00 492 90 202

718.0910 719.00 500 90 203

717.9989 718.00 492 95 204

718.0004 718.97 492 95 205

701.0392 702.01 500 95 206

693.0389 693.03 492 95 207

733.1018 734.10 500 90 208

720.0702 721.10 500 95 209

664.0440 665.08 500 95 210

706.0910 707.09 500 90 211

665.0644 666.08 500 95 212

830.0989 831.11 500 95 213

679.0801 680.09 492 95 214

558.1274 559.21 500 99 215

600.1743 601.30 500 99 216

624.1180 625.28 500 99 217

640.0884 641.27 500 99 218

624.1180 625.31 500 99 219

592.0884 593.28 500 80 220

634.1354 635.36 500 90 221

658.0790 659.32 500 85 222

674.0494 675.31 500 80 223

658.0790 659.34 500 80 224

636.0379 639.30 492 90 225

678.0848 679.37 492 95 226

702.0284 703.34 492 95 227

717.9989 719.34 492 95 228

702.0284 705.35 492 95 229

684.0200 685.30 500 99 230

726.0669 727.41 500 99 231

750.0105 751.38 500 99 232

765.9810 767.36 500 99 233

750.0105 751.38 500 99 234

732.0200 733.38 500 99 235

755.0571 756.33 500 99 236

655.9887 657.32 492 95 237

765.9810 767.38 492 99 238

878.0810 879.45 500 99 239

641.9730 643.31 492 99 240

781.0840 782.39 500 99 241

768.0523 769.38 500 99 242

711.9897 713.37 500 99

Reduction and Oxidation of Fredericamycin Aldehyde (4)

Fredericamycin aldehyde (4) can be reacted with a common reducing agentsuch as sodium borohydrid in a solvent such as DMF or pyridine tohydroxymethyl fredericamycin (11). The reaction can be summarized as asingle pot reaction (iodate cleavage of fredericamycin tetrol (2) tofredericamycin aldehyde (4) (see diagram 2) and reduction withoutisolation of the intermediates to fredericamycin alcohol (11)).

Fredericamycin aldehyde (4) can be oxidized with the oxidizing agentsodium chlorite (NaClO₂), a buffer such as sodium dihydrogenphosphate inpresence of an alkene such as 2,3-dimethylbutene with very good yieldsto fredericamycin carboxylic acid (12). The usually employed oxidationmethods such as those being used in preparative chemistry for theoxidation of aldehydes to carboxylic acids (oxidation with chromium(VI)compounds, manganese(VII) compounds as well as peroxo acid) did not leadto success. Only the use of the above described oxidation methodprovided the desired product. The literature describes oxidations of2-pyridone-6-aldehydes with silver ions and potassium permanganate in analkaline medium. This method, however, is not suited for fredericamycinand its derivatives since fredericamycin (1) contains base-labile(-reactive) groups (OH groups) causing undesired side reactions.

The potassium salt of the fredericamycin acid (13) was obtainedaccording to a common method by stoichiometric neutralization.

Substitution in the B Ring

Fredericamycin (1) can be reacted with halogenation agents such asN-bromosuccinimide (NBS) and N-iodosuccinimide (NIS) with good yields tothe substituted 5-bromo or 5-iodo fredericamycin derivatives (14) and(15) (diagram 6). The fredericamycin aldehyde (4) and (36) can betransformed with elemental bromine, NBS, BrI, NIS, and NCS to theappropriate halogen-substituted fredericamycin aldehyde (37), (38) and(39).

The appropriate fluorine compound is accessible, too.

Both of the two following fredericamycin compounds (23) and (24) arealso precursors. (23) is the precursor for an amino acid-linkedfredericamycin derivative.

The preparation of (23) may be recognized as proof that the aldehyde (4)may be reacted with phosphorylides according to Wittig or Wittig-Horner(see diagram 7).

The compound (24) is the precursor of an N-methylated fredericamycinderivative (diagram 8).

Fredericamycin may be transformed by palladium/hydrogen almostquantatively to tetrahydro fredericamycin (25), and may be halogenatedin the nucleus according to the above described methods, e.g. to thebromine compound (26) (diagram 9):

Surprisingly it has also been found that the methoxy groups infredericamycin and the derivatives according to the invention can beexchanged under alkali or earth alkali acetate catalysis by oxygennucleophiles such as alcohols or polyols. Thereby, the alcohols cancarry a multitude of different substituents (table 4).

TABLE 4 UV_(max) Yield Example R1 R2 R3 (nm) m/e (%) 243

H

504 (M + H) 554 97 244

H

500 (M+) 582 96 245

H

500 (M + H) 568 70 246

H

504 (M + H) 597 36 247

Br

504 (M+) 632/634 71 248

H

500 (M + H) 566 91 249

H

499 (M+) 569 52 250

H

504 (M + H) 616 99 251

H

500 (M+) 580 99 252

H

499 (M + H) 622 20 253

H

500 (M + H) 669 99 254

H

504 (M + H) 653 48 255

H

504 (M + H) 594 50 256

H

499 (M + H) 632/634 99

Exchange of the Methoxy Group at the F Ring

The exchange of the methoxy groups at the F ring of the fredericamycinand at the derivatives is possible by primary, secondary or aromaticamines. Thereby, the components are stirred with the appropriate primaryor secondary amines at room temperature in DMF or in another inertsolvent. With aromatic amines, a catalysis with Lewis acids such asstannous(IV)chloride, etc. is required.

TABLE 5   R1

  Example I

257 I

258 Br

259 H

260 H

261 H

262 H

263 H

264 H

265 I

266 H

267 H

268 H

269 Br

270

Preparation of Heterocyclic Fredericamycin Derivatives

The fredericamycin aldehyde (4) can be reacted to pyridal acetone (271)according to Wittig or Wittig-Horner. Bromation with bromine in DMFyields the dibromo-derivative (272) substituted in the side chain and atthe B ring. With the appropriately substituted thioamides or thioureas,the respective thiazole derivatives (273-276) are accessible.

TABLE 6 R Example NH₂ 273 Ph 274 CH₃CONH 275 CH₃ 276

Preparation of Thioanalogoues of Fredericamycin Derivatives

By sulfurization of fredericamycin or its derivatives with Lawessonreagent or P₄S₁₀ in pyridine, the derivatives analogous to thiopyridoneare accessible (see diagram 13).

Fredericamycin (1) forms inclusion compounds such as (25) withpolysugars such as α-cyclodextrin, that have good water solubilitycompared to the original substance.

The dextrin inclusion compounds form easily if the components are mixedin the appropriate stoichiometric ratio in a suitable solvent such asDMSO (see diagram 11).

Biological Activity Against 12 Cancer Cell Lines:

LCL (H460, lung), MACL (MCF7, breast), LXFL (52L, lung), LXFA (629L,lung), MEXF (462NL, melanoma), MEXF (514L, melanoma), MAXF (401NL,breast), RXF (944L, renal), RXF (486L, renal), UXF (1138L, uterus), PRXF(PC3M, prostate), PRXF (22RV1).

Efficacy (Ic70) Averaged Over all Cell Lines in μg/mL at 5 TestConcentrations

TABLE 7 Example/reference IC70 μg/mL adriamycin 0.0210 cisplatin 37.1020fredericamycin 0.2790  1 0.1130  13 0.0050  14 0.0070  22 0.0080  230.0110 121 0.2020 127 0.1550 192 0.0750 196 0.0950 197 0.0340 198 0.2560203 0.1590 212 0.2100 214 0.0220 215 0.0720 217 0.1290 218 0.0760 2240.0470 225 0.1110 230 0.0910 232 0.3170 233 0.1000 234 0.0520 235 0.0810236 0.1210 265 0.1330 275 0.3680 276 0.0840

EXAMPLES Example 11-Desoxy-5-C-[(8R)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]pentitol(2)

Two hundred (200) mg (0.38 mmol) fredericamycin A (1) are dissolved in30 mL dichloromethane. After addition of 20 mL methanol and 4.4 mlwater, 350 mg (2.6 mmol) N-methylmorpholine-N-oxide are added. Undervigorous stirring, 0.2 ml of a 2.5% osmium(IV)oxide solution int-butanol is added dropwise. The reaction mixture is acidified with 2-3drops of trifluoracetic acid. After stirring for 48 hours, the reactionis complete according to HPLC control (RP18, acetonitrile water (0.2%acetic acid)). The reaction mixture is added to 400 ml water undervigorous stirring, and the dark red crystalline solid is sucked offthrough a filter. Drying in HV. Yield: 195 mg (87% of the theoreticalvalue) dark red powder. ES⁻: M/e=606.2 (M+−H), λmax: 504.0.

Example 2Tri-potassium-1-desoxy-5-C-[(8R)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]pentitol(3)

Twelve (12.0) mg (19.8 μmol) fredericamycin tetrol (2) are dissolved in1.5 mL absolute pyridine under nitrogen atmosphere. The solution isgassed for 30 min with argon at 0° C. Under the argon atmosphere, 5.94mL of a 0.01 N KOH solution are added at once at 0° C. The reactionsolution immediately turns turquoise. The reaction mixture is stirredfor another 1 hour, and subsequently is frozen and lyophilized. Yield:13.2 mg (100% of the theoretical value); deep blue crystal mass.

Example 3(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde(4)

1.) Fifty (50) mg (82.3 μmol) tetrahydroxy fredericamycin (tetrol (2))are dissolved in 4 mL DMF. Under vigorous stirring, an aqueous sodiumiodate solution (300 mg NaIO₄ in 1 mL water) is added dropwise withinone hour. After 1 h stirring at room temperature, 2 drops oftrifluoracetic acid are added. After stirring for another 30 min, thereaction solution is diluted with 3 ml DMF, and 150 mg NaIO₄ dissolvedin 0.5 ml water are added. After another hour, 100 mL water are added.The supernatant over the precipitate is sucked off, and dryed in HV.Dark red crystal powder. Yield: 41 mg (100% of the theoretical value).M/e=501.3, UV_(max): 504.0 nm.

2.) One hundred and nine (109) mg (179 μmol) fredericamycin tetrol (2)are dissolved in 8 mL pyridine. 180 μL water are added. To the reactionmixture, 450 mg (1.08 mmol, 6 eq.) (polystryrylmethyl)trimethylammoniumperiodate resin are added. Then the mixture is stirred for 12 h at RT.The resin is filtered off; washing and concentrating until dry. Dark redresidue.

Yield: 89.9 mg (100% of the theoretical value). M/e=501.3, UV_(max):504.0 nm.

Example 41-[2-Oxo-2-((2E)-2-{[(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]methylene}ethyl]-dimethylaminotrifluoroacetate (118)

Twenty (20) mg (39.9 μmol) fredericamycin aldehyde (4) are dissolvedunder argon in 1.5 mL absolute DMF. Addition of 9.1 mg (47.9 μmol, 1.2eq.) acetylhydrazide dimethylammoniumchloride (Girard reagent D) and 20mg polyvinylpyridine (2% DVB). The mixture is stirred for 2.5 h. Then,27 mg (80 μmol, 2.0 eq.) aldehyde Wang resin (coating: 3.0 mmol/g) areadded and stirred for another 1 h. Then, the resin is filtered, andwashed 3× with DMF. Concentration in high vacuum. The residue isdissolved in 1 ml trifluoracetic acid, and concentrated after 10 minuntil dry.

Red solid; Yield: 28.5 mg (100%); ES⁺: M/e=601.3, UV_(max): 504.0 nm.

Example 51-[2-Oxo-2-((2E)-2-{[(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]methylene}hydrazino)-ethyl]pyridiniumchloride (119)

Fifteen (15) mg (29.9 μmol) fredericamycin aldehyde (4) are dissolved in3 mL DMF. At room temperature 7.5 mg (40.0 μmol) acethydrazinopyridiniumchloride (Girard reagent P) dissolved in 75 μL water are added. Thereaction mixture is stirred for 1.5 h at room temperature, and thecourse of the reaction is monitored by HPLC. When finished, acetic acidethyl ester is added to the reaction mixture, until a precipitationoccurs. After the crystallization is finished, the red solid is suckedoff.

Yield: 9.1 mg (44% of the theoretical value). M/e=635.2; λ_(max): 486.0.

Example 6(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeoxime (122)

Ten (10) mg (19.4 μmol) fredericamycin aldehyde (4) are dissolved in 2mL DMF. After addition of 3.1 mg (44.6 μmol) hydroxylammonium chloride,3.2 μl pyridine are added. Stirring for 2 h at room temperature. Thereaction mixture is added to 50 ml water and extracted 3 times withethyl acetate. After drying and concentration, a deep red amorphouscrystal powder was left (HPLC clean).

Yield: 7.4 mg (72% of the theoretical value). ES⁻: M/e=516.1; λ_(max):500.0 nm.

Example 7(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-O-methyloxime(8)

Ten (10) mg (19.4 μmol) fredericamycin aldehyde (4) are dissolved in 2mL DMF. After addition of 3.4 mg (40.7 μmol) O-methylhydroxylammoniumchloride and 3.2 μl pyridine, the reaction mixture is stirred for 2 h atroom temperature. Then, it is added to 100 ml water, and the supernatantis sucked off from the red precipitate (HPLC clean).

Yield: 7.6 mg (71% of the theoretical value). ES⁺: M/e=531.2; λ_(max):500.0.

Example 8(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-O-benzyloxime(9)

Ten (10) mg (19.4 μmol) fredericamycin aldehyde (4) are dissolved in 2mL DMF. After addition of 6.4 mg (43.2 μmol) O-benzylhydroxylammoniumchloride and 3.2 μl pyridine, the reaction mixture is stirred for 2 h atroom temperature. Then, it is added to 50 ml water, and the supernatantis sucked off from the red precipitate (HPLC clean).

Yield: 6.8 mg (57% of the theoretical value). ES⁺: M/e=607.2; λ_(max):504.0 nm.

Example 91-O-({(1E)-[(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]methylene}amino)-β-D-glucopyranose(10)

Two (2.0) mg (4.0 μmol) fredericamycin aldehyde (4) are dissolved in 150μL DMF, and 0.86 mg (4.4 μmol) β-aminoxy-D-glucopyranose is added. Themixture is stirred for 24 h at room temperature, and 5 mg (15.0 μmol)aldehyde Wang resin (coating: 3.0 mmol/g) is added. After stirring foranother 3 h, the resin is filtered off, washed with DMF, and thefiltrate is concentrated in high vacuum until dry.

Yield: 2.7 mg (99% of the theoretical value). red powder; ES⁻:M/e=678.1; λ_(max): 504.0 nm.

Example 10(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone(11)

Thirty (30) mg (49.4 μmol) tetrahydroxy fredericamycin (2) weredissolved in 2 mL pyridine. Twenty (20) mg (93.0 μmol) sodiummetaperiodate dissolved in 0.3 ml water are added. After stirring for 4h, 10 mg (260 μmol) sodium borohydride are added. After 12 h,concentration until dry, and the residue is separated by preparativeHPLC.

Yield: 2.6 mg (13% of the theoretical value) red powder. ES⁻: M/e=503.2;λ_(max): 504.0 nm.

Example 11(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carboxylicacid (12)

Fifteen (15) mg (29.9 μmol) fredericamycin aldehyde (4) are dissolved in1 mL dichloromethane and 0.5 ml t-butanol. Addition of 250 μl2,4-dimethylbutene. Under stirring at room temperature, a solution of6.0 mg (53.1 μmol) sodium chlorite (80%) and 5.1 mg sodiumhydrogenphosphate in 250 μl water are added dropwise.

After 2.5 h, again a solution of 10.0 mg (88.5 μmol) sodium chlorite and5 mg sodium dihydrogenphosphate in 200 μl water are added. Afteraltogether 4 h, it is put on water, and extracted with ethyl acetate.

The raw mixture was purified by preparative HPLC (RP18,acetonitrile-water-acetic acid). Red amorphous powder.

Yield: 68.3 mg (53.5% of the theoretical value). E: M/e=516.1; λ_(max):504.0 nm.

Example 12Potassium(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carboxylate(13)

6.9 mg (13.3 μmol) Fredericamycin carboxylic acid (12) are dissolved in5 mL DMF under nitrogen. At room temperature and under oxygen exclusionand vigorous stirring, 1.27 mL (12.7 μmol) of an aqueous 0.01 N KOHsolution is added dropwise. It is stirred for 15 minutes at roomtemperature, and concentrated in high vacuum until dry.

Yield: 7.40 mg (100% of the theoretical value). E: M/e=516.1; λ_(max):504.0 nm.

Example 13(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone(14)

Twenty (20) mg (37.1 μmol) fredericamycin (1) were dissolved in 250 μlDMF, and then 6.3 mg (35.3 μmol) N-bromosuccinimide in 250 μl DMF wereadded within one hour at 0° C. The reaction was stirred in a slowlythawing ice bath over night. Then, the DMF is removed in high vacuum,and the residue is purified by preparative HPLC.

Yield: 7 mg (32% of the theoretical value) red crystal mass.M/e=616.1/618.1; λ_(max): 486.0 nm.

Example 14(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone(15)

Eighty four (84) mg (158 μmol) fredericamycin (1) were dissolved in 1.0μl DMF, and then 33.0 mg (150.0 μmol) N-iodosuccinimide in 500 μl DMFwere added within one hour at 0° C. The reaction was stirred in a slowlythawing ice bath over night. Then, the DMF is removed in high vacuum,and the residue (120 mg (14) with a content of 80%) is purified bypreparative HPLC (gradient CH₃CN 50-90% over 16 min.)

Yield: 18 mg (17% of the theoretical value) red crystal mass. M/e=665.0;λ_(max): 484.0 nm.

Example 15Methyl-2-{[(benzyloxy)carbonyl]amino}-3-[(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]acrylate(23)

Sixty six (66) mg (200 μmol) Z-α-phosphonoglycine trimethylester aredissolved under argon in 1 mL absolute pyridine, and 25 μL1,1,3,3-tetramethylguanidine are added at 0° C. After 40 min. 20 mg (40μmol) fredericamycin aldehyde (4) is added at 0° C. After 15 min. 20 ml1 M acetic acid is added, and the mixture is extracted 3× with aceticacid. The raw product is purified by preparative HPLC (RP18,acetonitrile-water).

Yield: 10.0 mg (36% of the theoretical value). M/e=706.4; λ_(max): 492.0nm.

Example 16(8S)-9-hydroxy-4′,6′,9′-trimethoxy-2-methyl-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone(24)

Ten (10) mg (15 μmol) fredericamycin (1) were dissolved under protectivegas in 4 ml absolute DMF. At RT, 400 μl (4311 μmol) methyliodide and 81mg powdered potassium carbonate are added. The reactions mixture is thenstirred at RT for 20 h, and is then transferred onto water. Extractionwith ethyl acetate, and purification of the residue by separatingchromatography on chloroform/methanol 30/1.

Yield: 4 mg (37% of the theoretical value). Yellow residue. M/e=582.3;λ_(max): 368.0 nm.

Example 17 Fredericamycin A 1:2 complex with α-cyclodextrin (22)

Ten (10) mg fredericamycin (0.025 mMol) are added to a solution of 50 mgα-cyclodextrin (0.050 mMol) in 500 μl dimethylsulfoxide. The solution isthen diluted with 5 ml water. A stock solution prepared in such way canbe diluted as desired with water.

λ_(max)=504.0 nm.

Example 184′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde(4-methylpiperazine-1-yl)hydrazone(111)

Five (5) mg (9.42 μmol) fredericamycin aldehyde (4) are dissolved in 500μl DMF and 25 μl trifluoracetic acid. At room temperature, 1.30 mg (11.3μmol) 1-amino-4-methyl-piperazine is added. After stirring for 4.5 h atroom temperature, 1 equivalent each of Wang aldehyde resin andsulfonohydrazide resin is added and stirred for 2 h.

Filtration and concentration of the reaction solution at high vacuum.

Red powder. Yield: 5.4 mg (91% of the theoretical value). M/e=599(M+H)⁺; λ_(max): 504.0 nm.

Example 194′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-4,5-dihydro-1H-imidazole-2-yl-hydrazone(123)

Five (5.00) mg (9.42 μmol) fredericamycin aldehyde (4) are dissolved in500 μl DMF and 25 μl trifluoracetic acid. At room temperature, 2.05 mg(11.3 μmol) 2-hydrazino-2-imidazolin hydrobromide is added. Afterstirring for 4.5 h at room temperature, 1 equivalent each of Wangaldehyde resin and sulfonohydrazide resin are added and stirred for 2 h.Separation of the resin by filtration and concentration of the reactionsolution at high vacuum.

Red powder. Yield: 3.9 mg (67% of the theoretical value). M/e=584(M+H)⁺; λ_(max): 504.0 nm.

Example 204′,9,9′-Trihydroxy-6′-methoxy-3-{(E)-[(4-oxo-2-thioxo-1,3-thiazolidin-3-yl)imino]methyl}-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone(123)

Five (5.00) mg (9.42 μmol) fredericamycin aldehyde (4) are dissolved in500 μl DMF and 25 μl trifluoracetic acid. At room temperature, 1.67 mg(11.3 μmol) 2N-aminorhodanide are added. After stirring for 4.5 h atroom temperature, 1 equivalent each of Wang aldehyde resin andsulfonohydrazide resin are added and stirred for 2 h.

Filtration and concentration of the reaction solution.

Red powder. Yield: 4.1 mg (65% of the theoretical value). M/e=599(M+H)⁺; λ_(max): 504.0 nm.

Example 214′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-O-(2-morpholine-4-ylethyl)oxime(27)

Five (5.00) mg (9.42 μmol) fredericamycin aldehyde (4) are dissolved in500 μl DMF and 25 μl trifluoracetic acid. At room temperature, 2.47 mg(11.3 μmol) N-(aminoxyethyl)morpholine dihydrochloride is added. Afterstirring for 4.5 h at room temperature, 1 equivalent of Wang aldehyderesin (3.1 mg, 9.4 μmol, coating 3.0 mmol/g) as well as 1 equivalentsulfonohydrazide resin (6.1 mg, 9.4 mmol, 1.5 mmol) are added andstirred for 2 h.

Filtration and concentration of the reaction solution.

Red powder. Yield: 6.1 mg (98% of the theoretical value). M/e=630(M+H)⁺; λ_(max): 504.0 nm.

Example 22(8S)-5-chloro-4′,6′,9′-trimethoxy-2-methoxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone(34)

Three hundred (300) mg (556.6 μmol) fredericamycin (1) are dissolvedunder argon in 10 μl DMF, and then 75.0 mg (556.6 μmol)N-chlorosuccinimide are added. The reaction is stirred for 5 h at 40° C.The reaction mixture is then added to 400 ml methanol/water 1:1, and thered precipitate is sucked off and dried at high vacuum.

Yield: 305 mg (96% of the theoretical value) red crystal mass.M/e=573/575; λ_(max): 504.0 nm.

Example 23(8S)-5-fluoro-4′,9,9′-trihydroxy-6′-methoxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone(35)

Fifty (50) mg (92.8 μmol) fredericamycin (1) are dissolved in 5 ml DMFunder argon, and then 33.0 mg (93.5 μmol)1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) Selectfluor® is added. The reaction is stirredfor 24 h at room temperature. The reaction mixture is then added to 200ml water, and is extracted with ethyl acetate. The concentrated rawproduct is purified by preparative HPLC (RP18, acetonitrile-water-aceticacid).

Yield: 7.1 mg (14% of the theoretical value) red crystal mass. M/e=557;λ_(max): 504.0 nm.

Example 241-Desoxy-5-C-[(8R)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]-pentitol(36)

Hundred twenty (120) mg (209 mmol) chlorofredericamycin (34) aredissolved in 25.0 ml dichloromethane. After addition of 3.6 ml methanoland 0.8 ml water, 197 mg (1.46 mmol) N-methylmorpholine-N-oxide isadded. Under vigorous stirring, 0.12 ml of a 2.5% solution ofosmium(IV)oxide in t-butanol is added dropwise. After stirring for 27hours, the reaction is complete, according to HPLC monitoring (RP18,acetonitrile-water (0.2% acetic acid)). The reaction mixture is added to200 ml water under vigorous stirring, and the dark red solid is suckedoff Drying in HV.

Yield: 101 mg (75% of the theoretical value) dark red powder.M/e=641/643; λ_(max): 504.0.

Example 25(8S)-4′,9,9′-trihydroxy-5-bromo-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde(37)

Hundred (100) mg (200 μmol) fredericamycin aldehyde (4) are dissolvedunder argon in 5 ml DMF. Then, 200 μl of a 1M bromine solution in DMF isadded. After stirring for 1.5 h at RT, another 20 μl bromine solutionare added. According to HPLC monitoring, the reaction mixture iscomplete after 3.5 h.

Add to 150 ml water, and shake out with dichloromethane.

Yield: 96 mg (83% of the theoretical value) dark red powder.M/e=579/581; λ_(max): 504.0.

Example 261,2,3,4-Tetrahydro-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone(26)

Eight (8.0) mg (0.0128 mmol) 1,2,3,4-tetrahydrofredericamycin (25) aredissolved in 1 ml absolute DMF under nitrogen. Then a solution of 2.3 mg(0.0128 mmol) bromine in 0.25 ml DMF is added dropwise to the solution.Stirring at room temperature over 24 h. The reaction mixture isconcentrated to half volume in high vacuum, and is then transferred onto100 ml water. The supernatant is sucked off from the precipitate anddried in a vacuum.

Red crystal powder 8.1 mg (88% of the theoretical value) m/e=621/623;λ_(max): 499 nm.

Example 27(8S)-4′,9,9′-trihydroxy-6′-benzylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone

Twenty (20) mg (37.1 μmol) fredericamycin are dissolved in 1 ml DMFunder argon, then 4.76 mg (44.50 μmol) benzylamine are added at roomtemperature. According to HPLC (RP18, acetonitrile/water), a homogenousnew product has formed after 3 h. The reaction mixture is concentratedat high vacuum until dry.

Red crystal mass; Yield: 23 mg (100% of the theoretical value) M/e=615.3(M+H); λ_(max): 492 nm.

Example 28(8S)-5-chloro-4′,9,9′-trihydroxy-6′-benzylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone

Five (5.0) mg (8.71 μmol) 5-chlorofredericamycin are dissolved in 1 mlDMF under argon, then 1.12 mg (10.45 μmol) benzylamine are added at roomtemperature. After 29 h, the reaction mixture is concentrated at highvacuum until dry.

Red crystal mass; Yield: 5 mg (89% of the theoretical value) M/e=649.1(M+H); λ_(max): 492 nm.

Example 28 Translator: 28a(8S)-4′,9,9′-trihydroxy-6′-ethanolamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone

Ten (10) mg (18.6 μmol) fredericamycin are dissolved in 1 ml DMF underargon, then 1.36 mg (22.3 μmol) ethanolamine are added at roomtemperature. According to HPLC (RP18, acetonitrile/water), a homogenousnew product has formed after 3 h. The reaction mixture is concentratedat high vacuum until dry.

Red crystal mass; Yield: 9 mg (85% of the theoretical value) M/e=569.3(M+H); λ_(max): 500 nm.

Example 29(8S)-4′,9,9′-trihydroxy-6′-(4-piperidylmethylamino)-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone

Ten (10) mg (18.6 μmol) fredericamycin are dissolved in 1 ml DMF underargon, then 2.7 μl (22.3 μmol) 4-aminomethylpiperidine are added at roomtemperature. The reaction mixture is concentrated at high vacuum untildry after 24 h.

Red crystal mass; Yield: 11 mg (99% of the theoretical value) M/e=622.3(M+H); λ_(max): 492 nm.

Examples 100-142

The compounds 100-142 can be generated analogously to examples 7, 8, 9,10, 18, 19 and 20:

Example 1004′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydepyridine-2-yl-hydrazone(100)

Yield: (95% of the theoretical value) MS: M/e=593.1; λ_(max): 500.0 nm.

Example 1014′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde[4-(trifluoromethyl)pyrimidine-2-yl]hydrazone(101)

Yield: (95% of the theoretical value) MS: M/e=562.1; λ_(max): 500.0 nm.

Example 102N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]pyridyl-3-carbohydrazine(102)

Yield: (95% of the theoretical value) MS: M/e=621.1; λ_(max): 492.0 nm.

Example 103N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]isonicotinohydrazine(103)

Yield: (95% of the theoretical value) MS: M/e=621.1; λ_(max): 500.0 nm.

Example 1044′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-1,2,4-triazole-4-ylhydrazone(104)

Yield: (80% of the theoretical value) MS: M/e=568.1; λ_(max): 500.0 nm.

Example 1054′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-4,5-dihydro-1H-imidazole-2ylhydrazone(105)

Yield: (95% of the theoretical value) MS: M/e=584.1; λ_(max): 492.0 nm.

Example 106N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]-2-furohydrazine(106)

Yield: (95% of the theoretical value) MS: M/e=610.0; λ_(max): 492.0 nm.

Example 1074-Amino-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]benzohydrazine(107)

Yield: (95% of the theoretical value) MS: M/e=635.1; λ_(max): 492.0 nm.

Example 1084′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydethiosemicarbazone(108)

Yield: (95% of the theoretical value) MS: M/e=558.0; λ_(max): 492.0 nm.

Example 109N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]thiophene-2-carbohydrazine(109)

Yield: (95% of the theoretical value) MS: M/e=626.0; λ_(max): 492.0 nm.

Example 1102-(1H-indole-3-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazine (110)

Yield: (95% of the theoretical value) MS: M/e=673.1; λ_(max): 492.0 nm.

Example 1114′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde(4-methylpiperazine-1-yl)hydrazone(111)

Yield: (95% of the theoretical value) MS: M/e=599.1; λ_(max): 492.0 nm.

Example 1122-oxo-2-{(2E)-2-[(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]-hydrazino}acetamide(112)

Yield: (95% of the theoretical value) MS: M/e=587.1; λ_(max): 492.0 nm.

Example 1134′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone(113)

Yield: (95% of the theoretical value) MS: M/e=632.0; λ_(max): 500.0 nm.

Example 114{(2E)-2-[(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]-hydrazino}acetonitrile(114)

Yield: (95% of the theoretical value) MS: M/e=583.1; λ_(max): 492.0 nm.

Example 1152-Amino-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]benzohydrazine(115)

Yield: (95% of the theoretical value) MS: M/e=635.1; λ_(max): 492.0 nm.

Example 1164′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-[2-morpholine-4-yl-ethyl]oxime (116)

Yield: (85% of the theoretical value) MS: M/e=630.1; λ_(max): 492.0 nm.

Example 117(2E)-2-[(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazinecarboximidamide(117)

Yield: (95% of the theoretical value) MS: M/e=558.1; λ_(max): 500.0 nm.

Example 1182-(Dimethylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazine(118)

Yield: (85% of the theoretical value) MS: M/e=601.1; λ_(max): 492.0 nm.

Example 1191-[2-Oxo-2-((2E)-2-{[(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene}hydrazino)ethyl]pyridiniumchloride (119)

Yield: (85% of the theoretical value) MS: M/e=635.1; λ_(max): 492.0 nm.

Example 120(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-methyloxime (120)

Yield: (90% of the theoretical value) MS: M/e=531.1; λ_(max): 492.0 nm.

Example 1214′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-benzyloxime (121)

Yield: (95% of the theoretical value) MS: M/e=607.1; λ_(max): 492.0 nm.

Example 1224′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeoxime (122)

Yield: (95% of the theoretical value) MS: M/e=517.1; λ_(max): 482.0 nm.

Example 1231-O-({(1E)-[(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene}amino)-β-D-glucopyranose(123)

Yield: (95% of the theoretical value) MS: M/e=679.1; λ_(max): 500.0 nm.

Example 1244′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-phenylsemicarbazone(124)

Yield: (95% of the theoretical value) MS: M/e=635.1; λ_(max): 492.0 nm.

Example 1254′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydesemicarbazone(125)

Yield: (95% of the theoretical value) MS: M/e=559.1; λ_(max): 492.0 nm.

Example 1262-Piperidino-4-yl-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(126)

Yield: (95% of the theoretical value) MS: M/e=641.1; λ_(max): 492.0 nm.

Example 1274′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-(3-chlorobenzyl)oxime (127)

Yield: (95% of the theoretical value) MS: M/e=641.1; λ_(max): 492.0 nm.

Example 128N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]-(2-methyl-1,3-thiazole-4-yl)carbohydrazide(128)

Yield: (95% of the theoretical value) MS: M/e=641.1; λ_(max): 492.0 nm.

Example 1292-(1H-imidazole-1-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(129)

Yield: (90% of the theoretical value) MS: M/e=624.1; λ_(max): 500.0 nm.

Example 1302-(Acetylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]naphthalene]-3-yl)methylene]acetohydrazide(130)

Yield: (95% of the theoretical value) MS: M/e=615.1; λ_(max): 492.0 nm.

Example 1312-(4-Methylpiperazine-1-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(131)

Yield: (50% of the theoretical value) MS: M/e=656.1; λ_(max): 492.0 nm.

Example 1322-Morpholine-4-yl-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(132)

Yield: (60% of the theoretical value) MS: M/e=643.1; λ_(max): 492.0 nm.

Example 1332-(Methylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(133)

Yield: (70% of the theoretical value) MS: M/e=587.1; λ_(max): 492.0 nm.

Example 1342-[Isopropyl(methyl)amino]-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(134)

Yield: (70% of the theoretical value) MS: M/e=629.1; λ_(max): 492.0 nm.

Example 1354′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-[2-(dimethylamino)ethyl]oxime (127)

Yield: (90% of the theoretical value) MS: M/e=588.1; λ_(max): 492.0 nm.

Example 1364′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-[3-(4-(3-chlorophenyl)-piperazine-1-yl)propyl]oxime (136)

Yield: (85% of the theoretical value) MS: M/e=753.1; λ_(max): 492.0 nm.

Example 1374′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-[3-(dimethylamino)propyl]oxime (137)

Yield: (70% of the theoretical value) MS: M/e=602.1; λ_(max): 492.0 nm.

Example 138(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydepyridine-2-yl-hydrazone(138)

Yield: (95% of the theoretical value) MS: M/e=627.0; λ_(max): 500.0 nm.

Example 139(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde[4-(trifluoromethyl)pyrimidine-2-yl]hydrazone(139)

Yield: (95% of the theoretical value) MS: M/e=696.0; λ_(max): 500.0 nm.

Example 140(8S)-5-chloro-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]pyridyl-3-carbohydrazine(140)

Yield: (95% of the theoretical value) MS: M/e=655.0; λ_(max): 500.0 nm.

Example 141(8S)-5-chloro-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]isonicotinohydrazide(141)

Yield: (95% of the theoretical value) MS: M/e=655.0; λ_(max): 500.0 nm.

Example 142(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-1,2,4-triazole-4-ylhydrazone(142)

Yield: (90% of the theoretical value) MS: M/e=602.0; λ_(max): 500.0 nm.

Example 143(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-4,5-dihydro-1H-imidazole-2-ylhydrazone(143)

Yield: (95% of the theoretical value) MS: M/e=618.0; λ_(max): 500.0 nm.

Example 144(8S)-5-chloro-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]-2-furohydrazide(144)

Yield: (95% of the theoretical value) MS: M/e=644.0; λ_(max): 500.0 nm.

Example 145(8S)-5-chloro-4-amino-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]-benzohydrazide(145)

Yield: (95% of the theoretical value) MS: M/e=669.0; λ_(max): 500.0 nm.

Example 146(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydethiosemicarbazone(146)

Yield: (95% of the theoretical value) MS: M/e=609.0; λ_(max): 500.0 nm.

Example 147(8S)-5-chloro-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]thiophene-2-carbohydrazide(147)

Yield: (95% of the theoretical value) MS: M/e=660.0; λ_(max): 500.0 nm.

Example 148(8S)-5-chloro-2-(1H-indole-3-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(148)

Yield: (95% of the theoretical value) MS: M/e=707.1; λ_(max): 500.0 nm.

Example 149(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde(4-methylpiperazine-1-yl)hydrazone(149)

Yield: (95% of the theoretical value) MS: M/e=633.1; λ_(max): 500.0 nm.

Example 150(8S)-5-chloro-2-oxo-2-{(2E)-2-[4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazino}acetamide(150)

Yield: (95% of the theoretical value) MS: M/e=621.0; λ_(max): 500.0 nm.

Example 151(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone(151)

Yield: (95% of the theoretical value) MS: M/e=665.3; λ_(max): 500.0 nm.

Example 152(8S)-5-chloro-{(2E)-2-[4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazino}acetonitrile(152)

Yield: (95% of the theoretical value) MS: M/e=617.1; λ_(max): 500.0 nm.

Example 153(8S)-5-chloro-2-amino-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]benzohydrazide(153)

Yield: (95% of the theoretical value) MS: M/e=669.1; λ_(max): 500.0 nm.

Example 154(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-[2-morpholine-4-yl-ethyl)oxime (154)

Yield: (95% of the theoretical value) MS: M/e=664.1; λ_(max): 500.0 nm.

Example 155(8S)-5-chloro-(2E)-2-[(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazinecarboximidamide(155)

Yield: (95% of the theoretical value) MS: M/e=592.1; λ_(max): 500.0 nm.

Example 156(8S)-5-chloro-2-(dimethylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(156)

Yield: (95% of the theoretical value) MS: M/e=635.1; λ_(max): 500.0 nm.

Example 157(8S)-5-chloro-1-[2-oxo-2-((2E)-2-{[(8S)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazino)ethyl]pyridiniumchloride (157)

Yield: (95% of the theoretical value) MS: M/e=669.1; λ_(max): 500.0 nm.

Example 158(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-O-methyloxime(158)

Yield: (95% of the theoretical value) MS: M/e=565.0; λ_(max): 500.0 nm.

Example 159(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-O-benzyloxime(159)

Yield: (95% of the theoretical value) MS: M/e=641.1; λ_(max): 500.0 nm.

Example 160(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeoxime (160)

Yield: (95% of the theoretical value) MS: M/e=551.1; λ_(max): 500.0 nm.

Example 161(8S)-5-chloro-1-O-({(1E)-[(8S)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]amino)-β-D-glucopyranose(161)

Yield: (95% of the theoretical value) MS: M/e=713.1; λ_(max): 500.0 nm.

Example 162(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-phenylsemicarbazone(162)

Yield: (95% of the theoretical value) MS: M/e=669.1; λ_(max): 500.0 nm.

Example 163(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydesemicarbazone(163)

Yield: (90% of the theoretical value) MS: M/e=593.0; λ_(max): 500.0 nm.

Example 164(8S)-5-chloro-2-piperidino-4-yl-N′-[(1E)-[(8S)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(164)

Yield: (95% of the theoretical value) MS: M/e=675.1; λ_(max): 500.0 nm.

Example 165(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-(3-chlorobenzyl)oxime (165)

Yield: (90% of the theoretical value) MS: M/e=675.0; λ_(max): 500.0 nm.

Example 166(8S)-5-chloro-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]a-2-methyl-1,3-thiazole-4yl-carbohydrazide(166)

Yield: (95% of the theoretical value) MS: M/e=675.0; λ_(max): 500.0 nm.

Example 167(8S)-5-chloro-2-(1H-imidazole-1-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(1647)

Yield: (90% of the theoretical value) MS: M/e=658.1; λ_(max): 500.0 nm.

Example 168(8S)-5-chloro-2-(acetylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(164)

Yield: (95% of the theoretical value) MS: M/e=649.0; λ_(max): 500.0 nm.

Example 169(8S)-5-chloro-2-(4-methylpiperazine-1-yl)-n′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(169)

Yield: (60% of the theoretical value) MS: M/e=690.1; λ_(max): 500.0 nm.

Example 170(8S)-5-chloro-2-morpholine-4-yl-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(170)

Yield: (60% of the theoretical value) MS: M/e=677.1; λ_(max): 500.0 nm.

Example 171(8S)-5-chloro-2-(methylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(171)

Yield: (70% of the theoretical value) MS: M/e=621.1; λ_(max): 500.0 nm.

Example 172(8S)-5-chloro-2-[isopropyl(methyl)amino]-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(172)

Yield: (95% of the theoretical value) MS: M/e=675.1; λ_(max): 500.0 nm.

Example 173(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-[2-(dimethylamino)ethyl]-oxime (173)

Yield: (60% of the theoretical value) MS: M/e=622.0; λ_(max): 500.0 nm.

Example 174(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-[3-(4-(3-chlorophenyl)-piperazine-1-yl)propyl]-oxime (174)

Yield: (90% of the theoretical value) MS: M/e=787.1; λ_(max): 500.0 nm.

Example 175(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-[3-(dimethylamino)propyl]oxime (175)

Yield: (75% of the theoretical value) MS: M/e=636.1; λ_(max): 500.0 nm.

Example 176(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydepyridine-2-yl-hydrazone(176)

Yield: (95% of the theoretical value) MS: M/e=670.9; λ_(max): 500.0 nm.

Example 177(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde[4-(trifluoromethyl)pyrimidine-2-yl]hydrazone(177)

Yield: (95% of the theoretical value) MS: M/e=739.9; λ_(max): 500.0 nm.

Example 178(8S)-5-bromo-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]pyridyl-3-carbohydrazide(178)

Yield: (90% of the theoretical value) MS: M/e=699.0; λ_(max): 500.0 nm.

Example 179(8S)-5-bromo-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]isonicotinohydrazide(179)

Yield: (90% of the theoretical value) MS: M/e=699.0; λ_(max): 500.0 nm.

Example 180(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-1,2,4-triazole-4-ylhydrazone(180)

Yield: (70% of the theoretical value) MS: M/e=645.9; λ_(max): 492.0 nm.

Example 181(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-4,5-dihydro-1H-imidazole-2-ylhydrazone(181)

Yield: (95% of the theoretical value) MS: M/e=662.0; λ_(max): 492.0 nm.

Example 182(8S)-5-bromo-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]-2-furohydrazide(182)

Yield: (95% of the theoretical value) MS: M/e=688.9; λ_(max): 492.0 nm.

Example 183(8S)-5-bromo-4-amino-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]benzohydrazide(183)

Yield: (95% of the theoretical value) MS: M/e=713.0; λ_(max): 500.0 nm.

Example 184(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydethiosemicarbazone(184)

Yield: (95% of the theoretical value) MS: M/e=653.0; λ_(max): 500.0 nm.

Example 185(8S)-5-bromo-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]thiophene-2-carbohydrazide(185)

Yield: (95% of the theoretical value) MS: M/e=704.0; λ_(max): 492.0 nm.

Example 186(8S)-5-bromo-2-(1H-indole-3-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(186)

Yield: (95% of the theoretical value) MS: M/e=751.1; λ_(max): 500.0 nm.

Example 187(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde(4-methylpiperazine-1-yl)hydrazone(187)

Yield: (95% of the theoretical value) MS: M/e=677.1; λ_(max): 500.0 nm.

Example 188(8S)-5-bromo-2-oxo-2-{(2E)-2-[(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazino}acetamide(188)

Yield: (95% of the theoretical value) MS: M/e=665.0; λ_(max): 500.0 nm.

Example 189(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone(189)

Yield: (95% of the theoretical value) MS: M/e=709.9; λ_(max): 492.0 nm.

Example 190(8S)-5-bromo-{(2E)-2-[(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazino}acetonitrile(190)

Yield: (95% of the theoretical value) MS: M/e=661.0; λ_(max): 500.0 nm.

Example 191(8S)-5-bromo-2-amino-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]benzohydrazide(191)

Yield: (70% of the theoretical value) MS: M/e=713.0; λ_(max): 492.0 nm.

Example 192(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-[2-morpholine-4-yl-ethyl)oxime (192)

Yield: (95% of the theoretical value) MS: M/e=708.0; λ_(max): 500.0 nm.

Example 193(8S)-5-bromo-(2E)-2-[(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazinecarboximidamide(193)

Yield: (95% of the theoretical value) MS: M/e=636.0; λ_(max): 500.0 nm.

Example 194(8S)-5-bromo-2-(dimethylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(194)

Yield: (95% of the theoretical value) MS: M/e=679.0; λ_(max): 500.0 nm.

Example 195(8S)-5-bromo-1-[2-oxo-2-((2E)-2-{[(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene}hydrazino)ethyl]pyridiniumchloride (195)

Yield: (95% of the theoretical value) MS: M/e=713.0; λ_(max): 500.0 nm.

Example 196(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-methyloxime (196)

Yield: (95% of the theoretical value) MS: M/e=609.0; λ_(max): 492.0 nm.

Example 197(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-O-benzyloxime(197)

Yield: (95% of the theoretical value) MS: M/e=685.0; λ_(max): 492.0 nm.

Example 198(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeoxime (198)

Yield: (95% of the theoretical value) MS: M/e=595.0; λ_(max): 492.0 nm.

Example 199(8S)-5-bromo-1-O-({(1E)-[(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene}amino)-β-D-glucopyranose(199)

Yield: (90% of the theoretical value) MS: M/e=757.0; λ_(max): 500.0 nm.

Example 200(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-phenylsemicarbozone(200)

Yield: (90% of the theoretical value) MS: M/e=713.0; λ_(max): 500.0 nm.

Example 201(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydesemicarbazone(201)

Yield: (90% of the theoretical value) MS: M/e=637.0; λ_(max): 492.0 nm.

Example 202(8S)-5-bromo-2-piperidino-4-yl-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(201)

Yield: (90% of the theoretical value) MS: M/e=719.0; λ_(max): 500.0 nm.

Example 203(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-(3-chlorobenzyl)oxime (203)

Yield: (95% of the theoretical value) MS: M/e=718.0; λ_(max): 492.0 nm.

Example 204(8S)-5-bromo-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]-2-methyl-1,3-thiazole-4yl-carbohydrazide(204)

Yield: (95% of the theoretical value) MS: M/e=718.9; λ_(max): 492.0 nm.

Example 205(8S)-5-bromo-2-(1H-imidazole-1-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(205)

Yield: (95% of the theoretical value) MS: M/e=702.0; λ_(max): 500.0 nm.

Example 206(8S)-5-bromo-2-(acetylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(206)

Yield: (95% of the theoretical value) MS: M/e=693.0; λ_(max): 492.0 nm.

Example 207(8S)-5-bromo-2-(4-methylpiperazine-1-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(207)

Yield: (90% of the theoretical value) MS: M/e=734.1; λ_(max): 500.0 nm.

Example 208(8S)-5-bromo-2-morpholine-4-yl-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(208)

Yield: (95% of the theoretical value) MS: M/e=721.1; λ_(max): 500.0 nm.

Example 209(8S)-5-bromo-2-(methylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(209)

Yield: (95% of the theoretical value) MS: M/e=665.0; λ_(max): 500.0 nm.

Example 210(8S)-5-bromo-2-[isopropyl(methyl)amino]-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(210)

Yield: (95% of the theoretical value) MS: M/e=707.0; λ_(max): 500.0 nm.

Example 211(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-[2-(dimethylamino)ethyl]oxime (211)

Yield: (95% of the theoretical value) MS: M/e=666.0; λ_(max): 500.0 nm.

Example 212(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-[3-(4-(3-chlorophenyl)-piperazine-1-yl)propyl]oxime (212)

Yield: (95% of the theoretical value) MS: M/e=831.0; λ_(max): 500.0 nm.

Example 213(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-[3-(dimethylamino)propyl]oxime (213)

Yield: (95% of the theoretical value) MS: M/e=680.0; λ_(max): 492.0 nm.

Example 214(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-isopropyloxime (214)

Yield: (95% of the theoretical value) MS: M/e=559.2; λ_(max): 500.0 nm.

Example 215(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-n-hexyloxime (215)

Yield: (99% of the theoretical value) MS: M/e=601.3; λ_(max): 500.0 nm.

Example 216(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-(4-fluorobenzyl)oxime (216)

Yield: (99% of the theoretical value) MS: M/e=625.2; λ_(max): 500.0 nm.

Example 217(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-(4-chlorobenzyl)oxime (217)

Yield: (99% of the theoretical value) MS: M/e=641.2; λ_(max): 500.0 nm.

Example 218(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-(3-fluorobenzyl)oxime (218)

Yield: (99% of the theoretical value) MS: M/e=625.3; λ_(max): 500.0 nm.

Example 219(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-isopropyloxime (219)

Yield: (80% of the theoretical value) MS: M/e=593.2; λ_(max): 500.0 nm.

Example 220(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-n-hexyloxime (220)

Yield: (90% of the theoretical value) MS: M/e=635.3; λ_(max): 500.0 nm.

Example 221(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-(4-fluorobenzyl)oxime (221)

Yield: (85% of the theoretical value) MS: M/e=659.3; λ_(max): 500.0 nm.

Example 222(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-(4-chlorobenzyl)oxime (222)

Yield: (80% of the theoretical value) MS: M/e=675.3; λ_(max): 500.0 nm.

Example 223(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-(3-fluorobenzyl)oxime (223)

Yield: (80% of the theoretical value) MS: M/e=659.3; λ_(max): 500.0 nm.

Example 224(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-isopropyloxime (224)

Yield: (90% of the theoretical value) MS: M/e=639.3; λ_(max): 492.0 nm.

Example 225(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-n-hexyloxime (225)

Yield: (95% of the theoretical value) MS: M/e=679.3; λ_(max): 492.0 nm.

Example 226(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-(4-fluorobenzyl)oxime (226)

Yield: (95% of the theoretical value) MS: M/e=703.3; λ_(max): 492.0 nm.

Example 227(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-(4-chlorobenzyl)oxime (227)

Yield: (95% of the theoretical value) MS: M/e=719.3; λ_(max): 492.0 nm.

Example 228(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-(3-fluorobenzyl)oxime (228)

Yield: (95% of the theoretical value) MS: M/e=705.3; λ_(max): 492.0 nm.

Example 229(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-isopropyloxime (229)

Yield: (99% of the theoretical value) MS: M/e=685.3; λ_(max): 500.0 nm.

Example 230(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-n-hexyloxime (230)

Yield: (99% of the theoretical value) MS: M/e=727.4; λ_(max): 500.0 nm.

Example 231(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-(4-fluorobenzyl)oxime (231)

Yield: (99% of the theoretical value) MS: M/e=751.3; λ_(max): 500.0 nm.

Example 232(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-(4-chlorobenzyl)oxime (232)

Yield: (99% of the theoretical value) MS: M/e=767.3; λ_(max): 500.0 nm.

Example 233(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-(3-fluorobenzyl)oxime (233)

Yield: (99% of the theoretical value) MS: M/e=751.3; λ_(max): 500.0 nm.

Example 234(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-benzyloxime (234)

Yield: (99% of the theoretical value) MS: M/e=733.3; λ_(max): 500.0 nm.

Example 235(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-[2-morpholine-4-yl-ethyl)oxime (235)

Yield: (99% of the theoretical value) MS: M/e=756.3; λ_(max): 500.0 nm.

Example 236(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-methyloxime (236)

Yield: (95% of the theoretical value) MS: M/e=657.3; λ_(max): 492.0 nm.

Example 237(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-(3-chlorobenzyl)oxime (237)

Yield: (99% of the theoretical value) MS: M/e=767.3; λ_(max): 492.0 nm.

Example 238(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeO-[3-(4-(3-chlorophenyl)-piperazine-1-yl)propyl]oxime (238)

Yield: (99% of the theoretical value) MS: M/e=879.4; λ_(max): 500.0 nm.

Example 239(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydeoxime (239)

Yield: (99% of the theoretical value) MS: M/e=643.3; λ_(max): 492.0 nm.

Example 240(8S)-5-iodo-2-(4-methylpiperazine-1-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(240)

Yield: (99% of the theoretical value) MS: M/e=782.3; λ_(max): 500.0 nm.

Example 241(8S)-5-iodo-2-morpholine-4-yl-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide(241)

Yield: (99% of the theoretical value) MS: M/e=782.3; λ_(max): 500.0 nm.

Example 242(8S)-5-iodo-2-oxo-2-{(2E)-2-[(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazino}acetamide(242)

Yield: (99% of the theoretical value) MS: M/e=713.3; λ_(max): 500.0 nm.

Example 243(8S)-4′,9,9′-trihydroxy-6′-ethoxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta-[b]-naphthalene]-1,1′-3′,5′8′(2H)-pentone(243)

Five (5) mg (0.0095 mmol) fredericamycin (1) are suspended in 2.0 mlethanol. Under N₂ atmosphere, 90 mg sodium acetate are added and boiledunder reflux. After a few minutes, the suspension turns into a deep bluesolution. After 24 h it is cooled, transferred onto water and shaken outwith ethyl acetate (0.1% CF₃COOH). After drying and concentration, achromatographically homogenous, red powder is left.

Yield: 5.0 mg (97% of the theoretical value) MS=554 (M+H)⁺; λ_(max):504.0 nm.

Example 244(8S)-4′,9,9′-trihydroxy-6′-n-butoxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(244)

Six (6) mg (0.0114 mmol) fredericamycin (1) are suspended in 3.0 mln-butanol. Under N₂ atmosphere, 50 mg potassium acetate are added andheated to 100° C. After a few minutes, the suspension turns into a deepblue solution. The solution is left for 1 h at this temperature, and isthen cooled. It is transferred onto water and shaken out with ethylacetate (0.1% CF₃COOH). After drying and concentration, achromatographically homogenous red powder is left.

Yield: 6.2 mg (96% of the theoretical value) MS=582 (M)⁺; λ_(max): 500.0nm.

Example 245(8S)-4′,9,9′-trihydroxy-6′-n-isopropyloxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(245)

Five (5) mg (0.0095 mmol) fredericamycin (1) are suspended in 3.0 mln-propanol. Under N₂ atmosphere, 50 mg potassium acetate (anhydrous) areadded and heated to 80° C. After a few minutes, the suspension turnsinto a deep blue solution. The solution is left for 48 h at thistemperature, and is then cooled. It is transferred onto water and shakenout with ethyl acetate (0.1% CF₃COOH). After drying and concentration, achromatographically homogenous red powder is left.

Yield: 3.7 mg (70% of the theoretical value) MS=568 (M+H)+; λ_(max):500.0 nm.

Example 246(8S)-4′,9,9′-trihydroxy-6′-(2-dimethylaminoethoxy)-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(246)

6.1 mg (0.01159 mmol) fredericamycin (1) are suspended in 3.5 mlN,N-Dimethylaminoethanol. Under N₂ atmosphere, 52 mg anhydrous potassiumacetate are added and heated to 80° C. After a few minutes, thesuspension turns into a deep blue solution. The solution is left for 1.5h at this temperature, and is then cooled. It is transferred onto waterand shaken out with ethyl acetate (0.1% CF₃COOH). After drying andconcentration, a chromatographically homogenous red powder is left.

Yield: 2.4 mg (36% of the theoretical value); MS=597 (M+H)+; λ_(max):504.0 nm.

Example 247(8S)-5-bromo-4′,9,9′-trihydroxy-6′-(2-dimethylaminoethoxy)-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(247)

Ten (10.0) mg (0.019 mmol) bromofredericamycin (14) are suspended in 3.0ml ethanol. Under N₂ atmosphere, 50 mg anhydrous potassium acetate areadded and heated to 80° C. After a few minutes, the suspension turnsinto a deep blue solution. The solution is left for 48 h at thistemperature, and is then cooled. It is transferred onto water and shakenout with ethyl acetate (0.1% CF₃COOH). After drying and concentration, achromatographically homogenous red powder is left.

Yield: 7.2 mg (71% of the theoretical value); MS=632/634 (M+H)⁺;λ_(max): 504.0 nm.

Example 248(8S)-4′,9,9′-trihydroxy-6′-allyloxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(248)

9.6 mg (0.01824 mmol) fredericamycin (1) are suspended in 3.0 ml allylalcohol. Under N₂ atmosphere, 58 mg anhydrous potassium acetate areadded and heated to 70° C. After a few minutes, the suspension turnsinto a deep blue solution. The solution is left for 2.5 h at thistemperature, and is then cooled. It is transferred onto water and shakenout with ethyl acetate (0.1% CF₃COOH). After drying and concentration, achromatographically homogenous red powder is left.

Yield: 9.2 mg (91% of the theoretical value); MS=566 (M+H)+: λ_(max):500.0 nm.

The compounds 249, 250, 251, 252, 253, 254, 255 were generatedanalogously to the instructions 244-248:

Example 249(8S)-4′,9,9′-trihydroxy-6′-(2-hydroxyethoxy)-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(249)

Yield: 5.2 mg (52% of the theoretical value); MS=569 (M)⁺; λ_(max):499.0 nm.

Example 250(8S)-4′,9,9′-trihydroxy-6′-benzyloxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(250)

Yield: 10.2 mg (99% of the theoretical value); MS=616 (M+H)+; λ_(max):504.0 nm.

Example 251(8S)-4′,9,9′-trihydroxy-6′-cyclopropylmethoxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(251)

Yield: 12.9 mg (99% of the theoretical value); MS=580 (M)+; λ_(max):500.0 nm.

Example 2521-Desoxy-5-C-[(8R)-4′,9,9′-trihydroxy-6′-ethoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6′,7′,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]pentitol(252)

Yield: 2.0 mg (20% of the theoretical value); MS=622 (M+H)+; λ_(max):499.0 nm.

Example 253(8S)-4′,9,9′-trihydroxy-6′-(2-t-butoxycarbonylaminoethoxy)-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(253)

Yield: 12.9 mg (99% of the theoretical value); MS=669 (M)⁺; λ_(max):500.0 nm.

Example 254(8S)-4′,9,9′-trihydroxy-6′-(2-N,N-diisopropylaminoethoxy)-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(249)

Yield: 5.8 mg (48% of the theoretical value); MS=653 (M+H)+; λ_(max):500.0 nm.

Example 2551-Desoxy-5-C-[(8R)-4′,9,9′-trihydroxy-6′-ethoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]pentitol(255)

Yield: 5.5 mg (50% of the theoretical value); MS=594 (M+H)⁺; λ_(max):500.0 nm.

Example 256(8S)-4′,9,9′-trihydroxy-6′-(2-bromoethoxy)-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(256)

10.6 mg (0.02014 mmol) fredericamycin (1) are suspended in 2.0 mlbromoethanol. Under N₂ atmosphere, 150 mg anhydrous potassium acetateare added and heated to 120° C. After a few minutes, the suspensionturns into a deep blue solution. After 12 hours, addition of another 150mg potassium acetate. The solution is left for another 12 h at thistemperature, and is then cooled. It is transferred onto water and shakenout with ethyl acetate (0.1% CF₃COOH). After drying and concentration, achromatographically homogenous red powder is left.

Yield: 11.5 mg (99% of the theoretical value); MS=632/634 (M+H)⁺;λ_(max): 499.0 nm.

Example 257(8S)-5-iodo-4′,9,9′-trihydroxy-6′-cyclopropylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(257)

Five (5.0) mg (7.5 μmol) 5-iodofredericamycin (15) are dissolved underargon in 1.0 ml anhydrous DMF. After addition of 0.64 mg (11.2 μmmol)cyclopropylamine, it is stirred at room temperature for 3 h. Excesscycloprolylamine and DMF are removed at high vacuum. After drying andconcentration, a chromatographically homogenous red powder is left.

Yield: 5.1 mg (99%); MS=691.3 (M+H)+; λ_(max): 504.0 nm.

Example 258(8S)-5-iodo-4′,9,9′-trihydroxy-6′-n-butylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(258)

Five (5.0) mg (7.5 μmol) 5-iodofredericamycin (15) are dissolved underargon in 1.0 ml anhydrous DMF. After addition of 0.82 mg (11.2 μmmol)n-butylamine, it is stirred at room temperature for 20 h. Excessn-butylamine and DMF are removed at high vacuum. After drying andconcentration, a chromatographically homogenous red powder is left.

Yield: 5.3 mg (99%); MS=707.3 (M+H)+; λ_(max): 504.0 nm.

Example 259(8S)-5-bromo-4′,9,9′-trihydroxy-6′-n-butylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(259)

Five (5.0) mg (8.1 μmol) 5-bromofredericamycin (15) are dissolved underargon in 1.0 ml anhydrous DMF. After addition of 0.89 mg (12.2 μmmol)n-butylamine, it is stirred at room temperature for 20 h. Excessn-butylamine and DMF are removed at high vacuum. After drying andconcentration, a chromatographically homogenous red powder is left.

Yield: 5.3 mg (99%); MS=659.4/661.4 (M+H)+; λ_(max): 504.0 nm.

Example 260(8S)-4′,9,9′-trihydroxy-6′-cyclopropylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(260)

Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in1.0 ml anhydrous DMF. After addition of 2.12 mg (37.2 μmmol)cyclopropylamine, it is stirred at room temperature for 2 h. Excesscyclopropylamine and DMF are removed at high vacuum. After drying andconcentration, a chromatographically homogenous red powder is left.

Yield: 5.1 mg (99%); MS=565.4 (M+H)+; λ_(max): 510.0 nm.

Example 261(8S)-4′,9,9′-trihydroxy-6′-anilino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(261)

Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in1.0 ml anhydrous DMF. After addition of 3.46 mg (37.2 μmmol) aniline and37.2 μg stannous(IV)chloride (1.0 M in CH₂Cl₂), it is heated to 60° C.The reaction mixture is stirred for 24 h, and then excessdiethanolaminomethyl polystyrene resin is added. Stir for 1 h. Exhaustoff the resin and wash with DMF. The organic phase is concentrated athigh vacuum. A chromatographically homogenous red powder is left.

Yield: 5.5 mg (99%); MS=601.1 (M+H)+; λ_(max): 504.0 nm.

Example 262(8S)-4′,9,9′-trihydroxy-6′-piperidino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(262)

Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in1.0 ml anhydrous DMF. After addition of 3.16 mg (37.2 mmol) piperidine,it is stirred for 22 h at room temperature. Excess amine and DMF areremoved in high vacuum. A chromatographically homogenous red powder isleft.

Yield: 5.5 mg (99%); MS=593.4 (M+H)⁺; λ_(max): 504.0 nm.

Example 263(8S)-4′,9,9′-trihydroxy-6′-dimethylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(263)

Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in1.0 ml anhydrous DMF. After addition of 1.67 mg (37.2 mmol)dimethylamine (2M in MeOH), it is stirred for 4 h at room temperature.Excess amine and DMF are removed in high vacuum. A chromatographicallyhomogenous red powder is left.

Yield: 5.5 mg (99%); MS=553.6 (M+H)+; λ_(max): 526.0 nm.

Example 264(8S)-4′,9,9′-trihydroxy-6′-isopropylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(264)

Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in1.0 ml anhydrous DMF. After addition of 2.19 mg (37.2 mmol)isopropylamine, it is stirred for 4 h at room temperature. Excess amineand DMF are removed in high vacuum. A chromatographically homogenous redpowder is left.

Yield: 5.2 mg (99%); MS=567.3 (M+H)+; λ_(max): 504.0 nm.

Example 265(8S)-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(265)

Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in1.0 ml anhydrous DMF. After addition of 0.34 mg (11.1 mmol) methylamine(2M in CH₃OH), it is stirred for 19 h at room temperature. Excess amineand DMF are removed in high vacuum. A chromatographically homogenous redpowder is left.

Yield: 5.0 mg (99%); MS=539.2 (M+H)+; λ_(max): 504.0 nm.

Example 266(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(266)

Five (5.0) mg (7.5 μmol) 5-iodofredericamycin (1) are dissolved underargon in 1.0 ml anhydrous DMF. After addition of 0.28 mg (9.0 mmol)methylamine (2M in CH₃OH), it is stirred for 2 h at room temperature.Excess amine and DMF are removed in high vacuum. A chromatographicallyhomogenous red powder is left.

Yield: 5.0 mg (99%); MS=665.2 (M+H)+; λ_(max): 492.0 nm.

Example 267(8S)-4′,9,9′-trihydroxy-6′-morpholino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(267)

Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in1.0 ml anhydrous DMF. After addition of 3.24 mg (37.2 mmol) morpholine,it is stirred for 18 h at room temperature. Excess amine and DMF areremoved in high vacuum. A chromatographically homogenous red powder isleft.

Yield: 5.5 mg (99%); MS=595.5 (M+H)+; λ_(max): 518.0 nm.

Example 268(8S)-4′,9,9′-trihydroxy-6′-amino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(268)

Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in1.0 ml anhydrous DMF. After addition of 0.67 mg (37.2 μmmol) ammonia (2Min EtOH), it is stirred for 24 h at room temperature. Excess ammonia andDMF are removed in high vacuum. A chromatographically homogenous redpowder is left.

Yield: 4.8 mg (99%); MS=525.4 (M+H)+; 504.0 nm.

Example 269(8S)-4′,9,9′-trihydroxy-6′-pyrrolidino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(269)

Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in1.0 ml anhydrous DMF. After addition of 0.99 mg (13.9 μmmol)pyrrolidine, it is stirred for 19 h at room temperature. Excess amineand DMF are removed in high vacuum. A chromatographically homogenous redpowder is left.

Yield: 5.3 mg (99%); MS=579.2 (M+H)+; λ_(max): 554.0 nm.

Example 270(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone(270)

Five (5.0) mg (8.1 μmol) 5-bromofredericamycin (1) are dissolved underargon in 1.0 ml anhydrous DMF. After addition of 0.70 mg (12.2 μmmol)cyclopropylamine, it is stirred for 5 h at room temperature. Excesscyclopropylamine and DMF are removed in high vacuum. Achromatographically homogenous red powder is left.

Yield: 5.0 mg (99%); MS=643.4/645.4 (M+H)⁺; λ_(max): 492.0 nm.

Example 2712-[Acetyl]-3-[(8S)-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]ethene(271)

79.5 mg (479 μmol) (2-oxo-propyl)-phosphonic acid dimethylester aredissolved under argon in 8 ml absolute pyridine, and 60.2 μl (479 μmol)1,1,3,3-tetramethylguanidine are added at 0° C. After 5 minutes, 80.0 mg(159.7 μmol) fredericamycin aldehyde (4) is added at 0° C. After 2hours, 100 ml 1 M hydrochloric acid are added, and the supernatant issucked off from the precipitate. Dry under high vacuum.

Yield: 60.0 mg (69% of the theoretical value); M/e=542.2; λ_(max): 492.0nm.

Example 2722-[Bromoacetyl]-3-[(8S)-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]ethene(272)

Fifty (50.0) mg (92.4 μmol) acetyl fredericamycin are dissolved underargon in 5 ml absolute DMF, and then 36.9 mg (231.1 μmol) bromine as a 1M bromine solution in DMF are added under exclusion of light. It isstirred for 23 h under exclusion of light, and then 100 ml water areadded. The precipitate is sucked off and dried under high vacuum.

Yield: 57.0 mg (87% of the theoretical value) red powder;M/e=697.9/699.9/701.9; M+; λ_(max): 504.0 nm.

Example 2732-[2-Amino-thiazole-4-yl]-3-[(8S)-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]ethene (273)

Twenty (20.0) mg (28.7 μmol) bromoacetyl fredericamycin (273) aredissolved under argon in 4 ml absolute DMF. At room temperature, first3.3 mg (43.0 μmol) thiourea, and then 20 mg IR120 H+ are added. After 2hours, it is filtered off the resin, and added to 50 ml water. Theprecipitate is dried under high vacuum. Red powder.

Yield: 18.0 mg (93% of the theoretical value); M/e=676.1/678.1; (M+H);λ_(max): 492.0 nm.

Example 2742-[2-Phenyl-thiazole-4-yl]-3-[(8S)-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]ethene(274)

Five (5.0) mg (7.2 μmol) bromoacetyl fredericamycin (273) are dissolvedunder argon in 1 ml absolute DMF. At room temperature, first 1.5 mg(10.8 μmol) thiobenzamide, and then 5 mg IR120 H+ are added. After 3.5h, addition of hydrazinosulfonyl resin, and stirring for 2 h. It isfiltered off the resin, and added to 10 ml water. The precipitate isdried under high vacuum. Red powder.

Yield: 3.0 mg (57% of the theoretical value); M/e=737.2/739.2; (M+H);λ_(max): 492.0 nm.

Example 2752-[2-Acetylamino-thiazole-4-yl]-3-[(8S)-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]ethene(275)

Five (5.0) mg (7.2 μmol) bromoacetyl fredericamycin (273) are dissolvedunder argon in 1 ml absolute DMF. At room temperature, first 1.3 mg(10.8 μmol) acetylthiourea, and then 5 mg IR120 H+ are added. After 22h, addition of hydrazinosulfonyl resin, and stirring for 2 h. It isfiltered off the resin, and added to 10 ml water. The precipitate isdried under high vacuum. Red powder.

Yield: 2.0 mg (39% of the theoretical value); M/e=718.3/720.4; (M+H);λ_(max): 492.0 nm.

Example 2762-[2-Methyl-thiazole-4-yl]-3-[(8S)-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]ethene (276)

Five (5.0) mg (7.2 μmol) bromoacetyl fredericamycin (273) are dissolvedunder argon in 1 ml absolute DMF. At room temperature, first 0.81 mg(10.8 μmol) thioacetamide, and then 5 mg IR120 H+ are added. After 2 h,addition of hydrazinosulfonyl resin, and stirring for 2 h. It isfiltered off the resin, and added to 10 ml water. The precipitate isdried at high vacuum. Red powder.

Yield: 3.0 mg (62% of the theoretical value); M/e=675.2/677.2; (M+H);λ_(max): 492.0 nm.

Example 277(8S)-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1-thio-,1′-3′,5′,8′(2H)-tetrone-thiofredericamycin(277)

Ten (10.0) mg (18.5 μmol) fredericamycin (1) are dissolved under argonin 2 ml absolute pyridine. After addition of 20.5 mg (92.5 mmol)phosphorous-V-sulfide, it is heated for 12 h to 60° C. Addition ofanother 20.5 mg (92.5 mmol) phosphorous-V-sulfide. According to HPLC(acetonitrile/water CF₃COOH), the reaction was complete after 1 h. It istransferred onto water and shaken out with ethyl acetate. Dry andconcentrate. Purple-red powder.

Yield: 5.0 mg (49% of the theoretical value); M/e=55.7; (M+H); λ_(max):504.0 nm.

Example A Water Solubility of the Fredericamycin Derivatives

The water solubility of the various fredericamycin derivatives can bedetermined in a 0.9% NaCl solution with a pH of 7.

The compounds (22) and (3) dissolve very well. Compound (6) dissolveswell, and compounds (2), (10), and (13) are soluble. Compounds (5), (7),(11) and (12) are sufficiently and markedly better soluble thanfredericamycin (compound (1)).

1. A compound according to the general formula Ia or Ib:

wherein in each R1 means H, C₁-C₆ alkyl, cycloalkyl, or C₁-C₄alkylcycloalkyl, R2 means H, C₁-C₁₄ alkyl, C₂-C₁₄ alkenyl, aryl, C₁-C₄alkylaryl, heteroaryl, C₁-C₄ alkylheteroaryl, C₂-C₄ alkenylheteroaryl,cycloalkyl, C₁-C₄ alkylcycloalkyl, heterocycloalkyl, C₁-C₄alkylheterocycloalkyl, C_(m)H_(2m+o−p)Y_(p)(with m=1 to 6, for o=1, p=1,to 2m+o; for m=2 to 6, o=−1, p=1 to 2m+o; for m=4 to 6, o=−2, p=1 to2m+o; Y=independently selected from the group consisting of halogen, OH,OR21, NH₂, NHR21, NR21R22, and SH, SR21), (CH₂)_(r)CH₂NHCOR21,(CH₂)_(r)CH₂OCOR21, (CH₂)_(r)CH₂NHCSR21, (CH₂)_(r)CH₂S(O)_(n)R21, withn=0, 1, 2, (CH₂)_(r)CH₂SCOR21, (CH₂)_(r)CH₂OSO₂—R21, (CH₂)_(r)CHO,(CH₂)_(r)CH═NOH, (CH₂)_(r)CH(OH)R21, —(CH₂)_(r)CH═NOR21,(CH₂)_(r)CH═NOCOR21, (CH₂)_(r)CH═NOCH₂CONR21R22,(CH₂)_(r)CH═NOCH(CH₃)CONR21R22, (CH₂)_(r)CH═NOC(CH₃)₂CONR21R22,(CH₂)_(r)CH═N—NHCO—R23, (CH₂)_(r)CH═N—NHC(O)NH—R23,(CH₂)_(r)CH═N—NHC(S)NH—R23, (CH₂)_(r)CH═N—NHC(NH)NH—R23,(CH₂)_(r)CH═N—NHC(NH)—R23, (CH₂)_(r)CH═N—NHCO—CH₂NHCOR21,(CH₂)_(r)CH═N—O—CH₂NHCOR21, (CH₂)_(r)CH═N—NHCS—R23, (CH₂)_(r)CH═CR24R25(trans or cis), (CH₂)_(r)COOH, (CH₂)_(r)COOR21, (CH₂)_(r)CONR21R22,—(CH₂)_(r)CH═NR21, (CH₂)_(r)CH═N—NR21R22,

and the (CH₂)_(r)-chain elongated residue(CH₂)_(r)CH═N—N—(C₃NX′R211R212R213R214) (with X′═NR215, O, S, and R211,R212, R213, R214, R215 being independently H or C₁-C₆ alkyl),—(CH₂)_(r)CH═N—NHSO₂ aryl, or —(CH₂)_(r)CH═N—NHSO₂ heteroaryl, with r=0,1, 2, 3, 4, 5, R21, R22 are independently H, C₁-C₁₄ alkyl, C₁-C₁₄alkanoyl, C₁-C₆ alkylhydroxy, C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆alkylamino-C₁-C₆ alkyl, C₁-C₆ alkylamino-di-C₁-C₆-alkyl, cycloalkyl,C₁-C₄ alkylcycloalkyl, heterocycloalkyl, C₁-C₄ alkylheterocycloalkyl,aryl, aryloyl, C₁-C₄ alkylaryl, heteroaryl, heteroaryloyl, C₁-C₄alkylheteroaryl, cycloalkanoyl, C₁-C₄ alkanoylcycloalkyl,heterocycloalkanoyl, C₁-C₄ alkanoylheterocycloalkyl, C₁-C₄ alkanoylaryl,C₁-C₄ alkanoylheteroaryl, mono- and di-sugar residues linked through a Catom which would carry an OH residue in the sugar, wherein the sugarsare independently selected from the group consisting of glucuronic acidand its stereoisomers at all optical atoms, aldopentoses, aldohexoses,including their desoxy compounds (as e.g. glucose, desoxyglucose,ribose, desoxyribose), or R21 and R22, together with the N, form a ringwith 4, 5, 6, 7, or 8 members, which may optionally contain stillanother heteroatom selected from the group N, O, and S, R23independently of R21, has the same meanings as R21, or CH₂-pyridiniumsalts, CH₂-tri-C₁-C₆ alkylammonium salts, CONH₂, CSNH₂, CN, or CH₂CN,R24 independently of R21, has the same meanings as R21, or H, CN, COCH₃,COOH, COOR21, CONR21R22, NH₂, or NHCOR21, R25 independently of R21, hasthe same meanings as R21, or H, CN, COCH₃, COOH, COOR21, CONR21R22, NH₂,or NHCOR21, R24, R25 together with the N, form a ring with 4, 5, 6, 7,or 8 members, which may optionally contain still another heteroatomselected from the group N, O, and S, R3 means H, F, Cl, Br, I, OH, OR31,NO₂, NH₂, NHR31, NR31R32, NHCHO, NHCOR31, NHCOCF₃, CH_(3−m)hal_(m) (withhal=Cl, F, and m=1, 2, 3), or OCOR31, R31, R32 are independently C₁-C₆alkyl, or R31 and R32, together with the N, form a ring with 4, 5, 6, 7,or 8 members, which may optionally contain still another heteroatomselected from the group N, O, and S, R5 means H, C₁-C₂₀ alkyl,cycloalkyl, C₂-C₂₀ alkenyl, C₂-C₁₀ alkinyl, C₁-C₄ alkylcycloalkyl,heterocycloalkyl, C₁-C₄ alkylheterocycloalkyl, aryl, C₁-C₄ alkylaryl,heteroaryl, C₁-C₄ alkylheteroaryl, C_(m)H_(2m+o−p)Y_(p) (with m=1 to 6,for o=1, p=1 to 2m+o; for m=2 to 6, o=−1, p=1 to 2m+o; for m=4 to 6,o=−2, p=1 to 2m+o; Y=independently selected from the group consisting ofhalogen, OH, OR51, NH₂, NHR51, NR51R52, SH, SR21), (CH₂)_(s)CH₂NHCOR51,(CH₂)_(s)CH₂NHCSR51, (CH₂)_(s)CH₂S(O)nR51, with n=0, 1, 2,(CH₂)_(s)CH₂SCOR51, (CH₂)_(s)CH₂OCOR51, (CH₂)_(s)CH₂OSO₂—R51,(CH₂)_(s)CH(OH)R51, (CH₂)_(s)COOH, (CH₂)_(s)COOR51, (CH₂)_(s)CONR51R52,with s=0, 1, 2, 3, 4, 5, mono- and di-sugar residues linked through a Catom which would carry an OH residue in the sugar, wherein the sugarsare independently selected from the group consisting of glucuronic acidand its stereo isomers at all optical atoms, aldopentoses, aldohexoses,including their desoxy compounds (as e.g. glucose, desoxyglucose,ribose, desoxyribose), with the mono-sugar residues such asaldopentoses, aldohexoses, including their desoxy compounds, with R51,R52 which are capable of independently adopting the meaning of R21, R22,R4, R6, R7 independently mean H, C₁-C₆ alkyl, CO—R41, R41 independentlyfrom R21, has the same meanings as R21, X means O, S, NH, N—R8, whereinR8 independently from R5 may adopt the same meaning as R5, or R5 and R8,together with the N, form a ring with 4, 5, 6, 7, or 8 members, whichmay optionally contain still another heteroatom selected from the groupN, O, and S, or X—R5 may together be H, Y means O, S, NR9, wherein R9may be H or C₁-C₆ alkyl, as well their stereoisomers, tautomers, andtheir physiologically tolerable salts or inclusion compounds, whereinthe residues for Formula Ia may not concomitantly adopt the followingmeaning, except in case of cyclodextrin inclusion compounds: R1: H,C₁-C₆ alkyl, R2: C₁-C₆ alkyl, C₂-C₆ alkenyl, R3: H, R4 and R6 identical,and independently H, C₁-C₆ alkyl, CO—R41, with R41 being C₁-C₆ alkyl,aryl, and R7 being H, C₁-C₆ alkyl, Y: O, and for Formula Ib: R1: H, R2:pentyl, 1-pentenyl, 3-pentenyl, 1,3-pentdienyl, R3: H, R4 and R6 beingH, and X—R5 being methoxy, Y: O.
 2. The compound according to claim 1,wherein Formula Ia or Ib adopts the stereochemistry of Formula IIa orIIb


3. The compound of Formula Ia, Ib, IIa, IIb according to claim 2,wherein R2 has a water solubility that is at least two times highercompared to R2 being CH═CH—CH═CH—CH₃, with all other residues beingmaintained.
 4. The compound according to claim 1, wherein R3 means F,Cl, Br, I, OH, OR31, NO₂, NH₂, NHR31, NR31R32, NHCHO, NHCOR31, NHCOCF₃,CH_(3−m)hal_(m) (with hal=Cl, F, and m=1, 2, 3), or OCOR31.
 5. Thecompound according to claim 1, wherein R3 means (CH₂)_(r)CHO,(CH₂)_(r)CH═NOH, —(CH₂)_(r)CH═NOR21, (CH₂)_(r)CH═NOCOR21,(CH₂)_(r)CH═NOCH₂CONR21R22, (CH₂)_(r)CH═NOCH(CH₃)CONR21R22,(CH₂)_(r)CH═NOC(CH₃)₂CONR21R22, (CH₂)_(r)CH═N—NHCO—R23,(CH₂)_(r)CH═N—NHC(O)NH—R23, (CH₂)_(r)CH═N—NHC(S)NH—R23,(CH₂)_(r)CH═N—NHC(NH)NH—R23, (CH₂)_(r)CH═N—NHC(NH)—R23,(CH₂)_(r)CH═N—NHCO—CH₂NHCOR21, (CH₂)_(r)CH═N—O—CH₂NHCOR21,(CH₂)_(r)CH═N—NHCS—R23, (CH₂)_(r)CH═CR24R25 (trans or cis),(CH₂)_(r)CH═NR21, (CH₂)_(r)CH═N—NR21R22,

and the (CH₂)_(r)-chain elongated residue(CH₂)_(r)CH═N—N—(C₃NX′R211R212R213R214) (with X′═NR215, O, S, and R211,R212, R213, R214, R215 being independently H or C₁-C₆ alkyl),(CH₂)_(r)CH═N—NHSO₂ aryl, (CH₂)_(r)CH═N—NHSO₂ heteroaryl, with r=0, 1,2, 3, 4,
 5. 6. The compound according to claim 1, wherein X means N orS, or X—R5 is OH.
 7. The compound according to claim 1, wherein R1 meansH, C₁-C₅ alkyl, cycloalkyl, R2 means C₁-C₅ alkyl, C₁-C₄ alkylaryl, C₂-C₅alkenyl, heteroaryl, C₁-C₄ alkylheteroaryl, CHF₂, CF₃, polyol sidechain, CH₂Y (Y═F, Cl, Br, I), CH₂NH₂, CH₂NR21R22, CH₂NHCOR23,CH₂NHCSR23, CH₂SH, CH₂S(O)_(n)R21, with n=0, 1, 2, CH₂SCOR21, CH₂OH,CH₂OR21, CH₂OSO₂—R21, CHO, CH(OR21)₂, CH(SR21)₂, CN, CH═NOH, CH═NOR21,CH═NOCOR21, CH═N—NHCO—R32, CH═CR24, R25 (trans or cis), COOH, COOR21,CONR21R22, —CH═NR21, —CH═N—NR21R22,

(with X′═NR215, O, S, and R211, R212, R213, R214, R215 beingindependently H or C₁-C₆ alkyl), —CH═N—NHSO₂ aryl, —CH═N—NHSO₂heteroaryl, or CH═N—NHCO—R23, R21, R22 independently mean C₁-C₆ alkyl,cycloalkyl, aryl, C₁-C₄ alkylaryl, heteroaryl, or C₁-C₄ alkylheteroaryl,R23 independently of R21, has the same meanings as R21, orCH₂-pyridinium salts, or CH₂-tri-C₁-C₆ alkylammonium salts, R24independently of R21, has the same meanings as R21, or H, CN, COCH₃,COOH, COOR21, CONR21R22, NH₂, or NHCOR21, R25 independently of R21, hasthe same meanings as R21, or H, CN, COCH₃, COOH, COOR21, CONR21R22, NH₂,or NHCOR21, R24, R25 together mean C₄-C₈ cycloalkyl, R3 means F, Cl, Br,I, NO₂, NH₂, or NHCOR31, R31 independently means C₁-C₆ alkyl, R5 meansH, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, C₁-C₆ alkenyl,C₁-C₆ alkinyl, C₁-C₄ alkylcycloalkyl, heterocycloalkyl, C₁-C₄alkylheterocycloalkyl, aryl, C₁-C₄ alkylaryl, heteroaryl, C₁-C₄alkylheteroaryl, C_(m)H_(2m+o−p)Y_(p) (with m=1 to 6, for o=1, p=1 to2m+o; for m=2 to 6, o=−1, p=1 to 2m+o; for m=4 to 6, o=−2, p=1 to 2m+o;Y=independently selected from the group consisting of halogen, OH, OR21,NH₂, NHR21, NR21R22, SH, SR21), hydroxyalkyl with one or more OH groups,R4, R6, R7 independently mean H, C₁-C₅ alkyl, or CO—R41, R41independently from R21, has the same meanings as R21, X means O, S, NH,or N—R8, Y means O, or S.
 8. The compound according to claim 1 in theform of an inclusion compound with cyclodextrin.
 9. Drugs containingcompounds according to claim 1, a carrier and adjuvants.
 10. Drugsaccording to claim 9 in combination with further agents for tumortreatment.
 11. A method of treating a tumor in a patient comprisingadministering to said patient an effective amount of a compoundaccording to claim 1, particularly of those that can be treated byinhibition of the topoisomerases I and/or II, and by which apoptosis isinduced.
 12. A method of treating parasites in a patient comprisingadministering to said patient an effective amount of a compoundaccording to claim 1, or a compound in which the following meanings canbe concomitantly adopted in case of Formula Ia: R1: H, C₁-C₆ alkyl, R2:C₁-C₆ alkyl, C₂-C₆ alkenyl, R3: H, R4 and R6 identical, andindependently H, C₁-C₆ alkyl, CO—R41, with R41 being C₁-C₆ alkyl, aryl,and R7 being H, C₁-C₆ alkyl, and in case of Formula Ib: R1: H, R2:pentyl, 1-pentenyl, 3-pentenyl, 1,3-pentdienyl, R3: H, R4 and R6 beingH, and X—R5 being methoxy.
 13. A method of treating immunosuppression ina patient comprising administering to said patient an effective amountof a compound according to claim 1, or a compound in which the followingmeanings can be concomitantly adopted in case of Formula Ia: R1: H,C₁-C₆ alkyl, R2: C₁-C₆ alkyl, C₂-C₆ alkenyl, R3: H, R4 and R6 identical,and independently H, C₁-C₆ alkyl, CO—R41, with R41 being C₁-C₆ alkyl,aryl, and R7 being H, C₁-C₆ alkyl, and in case of Formula Ib: R1: H, R2:pentyl, 1-pentenyl, 3-pentenyl, 1,3-pentdienyl, R3: H, R4 and R6 beingH, and X—R5 being methoxy.
 14. A method for treating neurodermitis in apatient comprising administering to said patient an effective amount ofa compound according to claim 1 or a compound in which the followingmeanings can be concomitantly adopted in case of Formula Ia: R1: H,C₁-C₆ alkyl, R2: C₁-C₆ alkyl, C₂-C₆ alkenyl, R3: H, R4 and R6 identical,and independently H, C₁-C₆ alkyl, CO—R41, with R41 being C₁-C₆ alkyl,aryl, and R7 being H, C₁-C₆ alkyl, and in case of Formula Ib: R1: H, R2:pentyl, 1-pentenyl, 3-pentenyl, 1,3-pentdienyl, R3: H, R4 and R6 beingH, and X—R5 being methoxy.